ARC (activity-regulated cytoskeleton-associated protein, Arg3.1) is a neuronal immediate-early gene product that is, structurally and functionally, a domesticated retrotransposon capsid protein. Its 396-residue chain folds into two lobes whose arrangement matches the capsid domain of retroviral Gag polyproteins, and tetrapod Arc genes derive from a vertebrate lineage of Ty3/gypsy retrotransposons; fly Arc genes come from a separate insect lineage of the same element family, so the two are convergent domestications rather than orthologues of a single cellular ancestor. The protein does two things that reflect that ancestry. First, it self-assembles. A short helical coil in the N-terminal domain drives oligomerisation beyond the dimer stage, and the assembled protein forms double-shelled capsids roughly 32 nm across that encapsidate RNA. RNA is required for efficient assembly, and the RNA taken up is not sequence-selective - abundant transcripts are packaged roughly in proportion to their abundance, with Arc's own mRNA prominent because it is abundant where Arc is made. Neurons release these capsids in extracellular vesicles; recipient neurons endocytose them, and the delivered mRNA reaches the cytoplasm where it can be translated on demand. Arc is therefore a vehicle for intercellular RNA transfer in the nervous system. Second, Arc weakens synapses. Induced within minutes of strong activity and delivered as mRNA to stimulated dendritic regions, the protein accumulates at the postsynaptic density and the lateral margins of dendritic spines, anchored to the membrane by palmitoylation of an N-terminal cysteine cluster rather than by a transmembrane segment. There it binds endophilin 2/3 and dynamin 2 through separate regions and accelerates clathrin- and dynamin-dependent endocytosis of AMPA-type glutamate receptors into early endosomes. Losing Arc raises surface AMPA receptor levels and slows their internalisation; raising Arc does the reverse. This single mechanism underlies the late, protein-synthesis-dependent phase of long-term potentiation, metabotropic-receptor long-term depression, homeostatic downscaling of synaptic strength during chronic inactivity, and the consolidation of long-term memory. Targeting is paradoxical and deliberate: CaMKII-beta in its calmodulin-free state recruits Arc preferentially to synapses that have fallen silent, so the protein prunes the weak rather than the active. A separate nuclear pool, controlled by a dedicated localisation signal, retention domain and export signal, raises promyelocytic leukaemia body formation and lowers GluA1 transcription, giving the same downscaling by a transcriptional route. During cerebellar development Arc mediates the final stage of climbing-fibre synapse elimination. Both activities depend on the same interface. Mutating the seven-residue oligomerisation motif abolishes capsid formation and also blocks Arc-facilitated endocytosis; CaMKII phosphorylation of the Gag N-lobe disrupts the same surface and switches high-order assembly off. Protein levels are held brief by ubiquitination - by RNF216/Triad3A at two adjacent lysines, and by UBE3A - so that the signal is transient. Outside the nervous system, Arc is confined to skin-migratory dendritic cells, where it accelerates migration through myosin II-dependent actin dynamics and thereby shapes T-cell activation.
Definition: The aggregation, arrangement and bonding together of protein subunits encoded by endogenous, non-viral genes to form a virus-like capsid, a non-infectious protein coat that surrounds nucleic acid.
Justification: GO already recognises the product of this process: GO:0170047 virus-like capsid is a cellular component whose definition explicitly names fly and tetrapod Arc. There is no corresponding biological-process term. The only capsid-assembly terms in the ontology are viral - GO:0019069 viral capsid assembly and its children GO:0039708 and GO:0039709 - and none of them can be used for a protein encoded by a host gene that assembles a non-infectious particle. As a result the assembly step of Arc, the step that every other Arc function depends on, has to be annotated as GO:0051260 protein homooligomerization, which is true of any trimer and says nothing about the shell. The same gap will be hit by every domesticated Gag gene as they are curated: fly Arc1 and Arc2, the PNMA/MOAP family, and PEG10 and the other retroelement-derived mammalian genes.
Parent term: protein-containing complex assembly
Supporting Evidence:
Definition: The action of a molecule that contributes to the structural integrity of a virus-like capsid, a non-infectious protein coat encoded by endogenous, non-viral genes that surrounds nucleic acid.
Justification: The molecular-function half of the same gap. GO:0039660 structural constituent of virion exists for viral capsid proteins, but a domesticated Gag protein cannot use it, so Arc's capsid role is annotated to the bare parent GO:0005198 structural molecule activity - a term shared with keratins, tubulins and ribosomal proteins. A sibling of GO:0039660 under GO:0005198 would make the annotation say what the structure actually is, and would pair with the CC term GO:0170047 that already exists.
Parent term: structural molecule activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001669 acrosomal vesicle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Arc protein was detected in the developing acrosome of mouse spermatids and in the acrosomal region, neck and principal piece of mature mouse sperm. That single mouse study is the entire basis of the claim; UniProt records the human location as 'Cytoplasmic vesicle, secretory vesicle, acrosome {ECO:0000250|UniProtKB:Q9WV31}', i.e. by similarity from mouse, and the SubCell-to-GO mapping then converts that by-similarity statement into a GO annotation on the human protein. Reason: Plausible and not contradicted, but three steps removed from any human observation and orthogonal to everything Arc is known for. The germ-cell pool is also biochemically different from the neuronal one - Arc is lost during capacitation and the acrosome reaction - so this is a distinct context rather than a refinement of the synaptic localisation. Peripheral. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0007 · UniProt SubCell keyword SL-0007, Acrosome SOURCE WEAK OR INFERRED The SubCell keyword Acrosome is the proximate source of this IEA. Its entry on the human record carries ECO:0000250|UniProtKB:Q9WV31, so the chain is mouse immunofluorescence (PMID:12493697) -> UniProt by-similarity on Q7LC44 -> SubCell keyword -> GO IEA. No human evidence exists at any point in that chain, and the underlying observation is a single 2003 study that has not been followed up. Supporting Evidence: PMID:12493697 In isolated mature sperm, arc is present in the acrosomal region of the sperm head, the centriole region of the neck, and the principal piece of the tail. file:human/ARC/ARC-uniprot.txt acrosome {ECO:0000250|UniProtKB:Q9WV31}. Cytoplasmic vesicle, clathrin- |
| GO:0003729 mRNA binding | IDA PMID:33175445 Arc self-association and formation of virus-like capsids are... | ACCEPT | Summary: Arc binds mRNA, and the binding is functionally coupled to its capsid activity rather than incidental. Eriksen et al. showed by single-molecule photobleaching that Arc mRNA drives Arc into higher-order oligomers, and that this depends on the same 7-residue N-terminal oligomerisation motif that is required for capsid formation. Pastuzyn et al. showed the converse in purified material: stripping nucleic acid from recombinant Arc suppresses capsid assembly and adding GFP mRNA back restores it. The binding is not sequence-selective - Arc capsids purified from bacteria package abundant cellular RNA roughly in proportion to its abundance - so mRNA binding here means 'binds mRNA as the RNA cargo of a Gag-like capsid', not 'recognises a specific transcript'. The GO term is still the right one: mRNA is what is demonstrably bound and what is demonstrably transferred between cells. Reason: RNA binding is one half of what a domesticated Gag protein does, and it is the half that makes the intercellular mRNA transfer possible. The IDA is on the human protein and FlyBase curators read the full text; the human anchor in that paper is the 0.95 A structure of the human oligomerisation coil, PDB 6YTU, which UniProt cross-references to Q7LC44 over residues 99-132. Core. Supporting Evidence: PMID:33175445 Furthermore, using single-molecule photobleaching, we show that Arc mRNA greatly enhances higher-order oligomerization in a manner dependent on the oligomerization motif. PMID:29328916 Stripping RNA resulted in significantly fewer fully-formed capsids (Figure 2E), suggesting that Arc capsids require RNA for normal assembly. PMID:29328916 suggesting that prArc capsids show little specificity for a particular mRNA, but encapsulate abundant RNA according to stoichiometry. |
| GO:0003729 mRNA binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from IPR023263, the family signature for Arc itself. The family has exactly one member per tetrapod genome and the mapping asserts of Arc what has been shown for Arc, so there is no family-level over-reach here: this is not a fold-to-activity leap across a diverse superfamily, it is a one-gene family whose defining member is an experimentally demonstrated RNA-binding capsid protein. Reason: The mapping agrees with the human IDA on the same term and with rat Arc's IDA on PMID:29328916. An IEA that lands on the same term as the direct evidence is doing its job. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR023263 · InterPro IPR023263, Activity-regulated cytoskeleton-associated protein (family) SUPPORTS TRANSFER IPR023263 is the Arc family signature, not a broad Gag superfamily signature; human ARC is the human member of that family (UniProt: DR InterPro; IPR023263; Arc). The InterPro2GO rule therefore transfers a property established on Arc itself. Supporting Evidence: PMID:29328916 Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. file:human/ARC/ARC-uniprot.txt SIMILARITY: Belongs to the ARC/ARG3.1 family. |
| GO:0003729 mRNA binding | ISS GO_REF:0000024 | ACCEPT | Summary: Curated sequence-similarity transfer from rat Arc, whose own annotation for this term is an IDA on Pastuzyn et al. 2018 - the study that purified recombinant rat Arc, showed it encapsidates RNA, and showed that stripping the RNA blocks capsid assembly. Human and rat Arc are both 396 aa and there is no mammalian paralogue to confuse. Reason: Sound donor, sound transfer, and the human protein independently carries an IDA for the same term. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA on PMID:29328916, the paper that demonstrated RNA encapsidation by purified recombinant rat Arc.. Supporting Evidence: PMID:29328916 Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. PMID:21834987 Unlike the other PMM genes we analysed in detail, ARC (activity-regulated cytoskeleton-associated protein) and ZRANB1 are each unique genes without closely related isoforms in mammals. |
| GO:0005198 structural molecule activity | IBA GO_REF:0000033 | ACCEPT | Summary: The node asserts that tetrapod Arc proteins are structural: they are the building block of a capsid shell. The single gene-level seed is human ARC itself, whose IDA on PMID:33175445 records that purified wild-type Arc forms capsids while an oligomerisation-motif mutant stops at dimers. This is the expected shape of a self-referential IBA: the target's own experimental annotation is one of the descendant evidences the PAINT curator used to place the node, and the IBA then adds the separate claim that the property is inherited from the tetrapod ancestor rather than being human-specific. Reason: Correct node, correct clade, correct term. GO:0005198 is defined as 'the action of a molecule that contributes to the structural integrity of a complex', which is exactly what a capsid protomer does. The term is generic only because GO has no non-viral counterpart to GO:0039660 structural constituent of virion - an ontology gap recorded in proposed_new_terms, not a defect in this annotation. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008562333 · PTHR15962 Arc IBD node, placed at Tetrapoda (taxon:32523) SUPPORTS TRANSFER Sole IBD node of PTHR15962, placed at Tetrapoda (taxon:32523). Its structural molecule activity assertion is seeded by human ARC's own IDA on PMID:33175445. Human ARC is a tetrapod Arc and sits inside the inheriting clade. The node deliberately excludes Drosophila Arc1 (Q7K1U0), which PANTHER places in the same family and subfamily but which is an independent Ty3/gypsy domestication; QuickGO confirms dArc1 carries no IBA from this node. The fly exclusion matters here specifically: dArc1 also forms capsids and carries its own IDA for GO:0005198 (FlyBase, PMID:31907439), but it acquired that property independently, and keeping the node at Tetrapoda is what keeps the convergence visible. UniProtKB:Q7LC44 · ARC (Homo sapiens), the target itself SUPPORTS TRANSFER The target's own IDA for this term (FlyBase, PMID:33175445) is one of the descendant evidences behind the IBD. Its presence in the WITH/FROM is correct and expected, marks experimental grounding on the target itself, and is not circular. Supporting Evidence: PMID:33175445 Purified wild-type Arc formed capsids as shown by transmission and cryo-electron microscopy, whereas mutant Arc with disruption of the oligomerization motif formed homogenous dimers. PMID:25864631 We report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. |
| GO:0005198 structural molecule activity | IDA PMID:33175445 Arc self-association and formation of virus-like capsids are... | ACCEPT | Summary: Direct evidence: purified Arc assembles into capsids by EM, and disrupting the 7-residue N-terminal oligomerisation motif reduces the protein to homogeneous dimers. The same mutation also abolishes Arc-facilitated endocytosis in neurons, which is what ties the structural role to the synaptic one. Reason: The defining molecular property of the protein. Cache is abstract-only and the abstract says 'mammalian Arc' without naming a species for the capsid preparations, but the paper's human anchor is real - PDB 6YTU is the human Arc 99-132 coil (UniProt cross-reference to Q7LC44; RCSB gives the source organism as Homo sapiens) - and FlyBase curators read the full text. Core. Supporting Evidence: PMID:33175445 Here, we identified a 28-amino-acid stretch in the mammalian Arc N-terminal (NT) domain that is necessary and sufficient for self-association. PMID:33175445 In conclusion, a helical coil in the Arc NT domain supports self-association above the dimer stage, mRNA-induced oligomerization, and formation of virus-like capsids. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A binary yeast two-hybrid interaction with TBX18 (a T-box transcription factor of the sclerotome and ureteric mesenchyme) from the HuRI reference interactome. UniProt records it as NbExp=3, which is three assay replicates inside that one screen, not three independent studies. There is no follow-up anywhere linking TBX18 to Arc biology: it does not appear in the Arc capsid, endocytosis, plasticity or nuclear literature, and it is not in UniProt's SUBUNIT block. Reason: Removed because GO:0005515 carries no functional information, not because the TBX18 interaction is false - the HuRI identification is reproducible and is retained in IntAct and in UniProt's INTERACTION block, where it belongs. MODIFY is not available here: the screen is an all-by-all two-hybrid assay with no functional follow-up on this pair, so there is no evidence-supported molecular function to replace the term with, and inventing one from interaction evidence alone is exactly what the policy forbids. The contrast is instructive: the partners that do carry mechanism - endophilin 2/3, dynamin 2, CaMKIIbeta, PSEN1 - sit in UniProt's SUBUNIT block only as 'By similarity' and have no human IPI row at all, so the human interaction record for this gene is inverted with respect to biological importance. The informative molecular function the record was missing is added separately as GO:0030674 protein-macromolecule adaptor activity, on the characterised partners rather than on these four. Supporting Evidence: file:human/ARC/ARC-uniprot.txt Q7LC44; O95935: TBX18; NbExp=3; file:human/ARC/ARC-uniprot.txt SUBUNIT: Homooligomer; homooligomerizes into virion-like capsids |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A binary yeast two-hybrid interaction with S100P (an EF-hand calcium-binding protein of placenta and epithelia) from the HuRI reference interactome. UniProt records it as NbExp=3, which is three assay replicates inside that one screen, not three independent studies. There is no follow-up anywhere linking S100P to Arc biology: it does not appear in the Arc capsid, endocytosis, plasticity or nuclear literature, and it is not in UniProt's SUBUNIT block. Reason: Removed because GO:0005515 carries no functional information, not because the S100P interaction is false - the HuRI identification is reproducible and is retained in IntAct and in UniProt's INTERACTION block, where it belongs. MODIFY is not available here: the screen is an all-by-all two-hybrid assay with no functional follow-up on this pair, so there is no evidence-supported molecular function to replace the term with, and inventing one from interaction evidence alone is exactly what the policy forbids. The contrast is instructive: the partners that do carry mechanism - endophilin 2/3, dynamin 2, CaMKIIbeta, PSEN1 - sit in UniProt's SUBUNIT block only as 'By similarity' and have no human IPI row at all, so the human interaction record for this gene is inverted with respect to biological importance. The informative molecular function the record was missing is added separately as GO:0030674 protein-macromolecule adaptor activity, on the characterised partners rather than on these four. Supporting Evidence: file:human/ARC/ARC-uniprot.txt Q7LC44; P25815: S100P; NbExp=3; file:human/ARC/ARC-uniprot.txt SUBUNIT: Homooligomer; homooligomerizes into virion-like capsids |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A binary yeast two-hybrid interaction with CSRP2 (a LIM-domain cysteine- and glycine-rich protein of smooth muscle) from the HuRI reference interactome. UniProt records it as NbExp=3, which is three assay replicates inside that one screen, not three independent studies. There is no follow-up anywhere linking CSRP2 to Arc biology: it does not appear in the Arc capsid, endocytosis, plasticity or nuclear literature, and it is not in UniProt's SUBUNIT block. Reason: Removed because GO:0005515 carries no functional information, not because the CSRP2 interaction is false - the HuRI identification is reproducible and is retained in IntAct and in UniProt's INTERACTION block, where it belongs. MODIFY is not available here: the screen is an all-by-all two-hybrid assay with no functional follow-up on this pair, so there is no evidence-supported molecular function to replace the term with, and inventing one from interaction evidence alone is exactly what the policy forbids. The contrast is instructive: the partners that do carry mechanism - endophilin 2/3, dynamin 2, CaMKIIbeta, PSEN1 - sit in UniProt's SUBUNIT block only as 'By similarity' and have no human IPI row at all, so the human interaction record for this gene is inverted with respect to biological importance. The informative molecular function the record was missing is added separately as GO:0030674 protein-macromolecule adaptor activity, on the characterised partners rather than on these four. Supporting Evidence: file:human/ARC/ARC-uniprot.txt Q7LC44; Q16527: CSRP2; NbExp=3; file:human/ARC/ARC-uniprot.txt SUBUNIT: Homooligomer; homooligomerizes into virion-like capsids |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: A binary yeast two-hybrid interaction with SH2D4A (an SH2-domain adaptor, also called PPP1R38) from the HuRI reference interactome. UniProt records it as NbExp=3, which is three assay replicates inside that one screen, not three independent studies. There is no follow-up anywhere linking SH2D4A to Arc biology: it does not appear in the Arc capsid, endocytosis, plasticity or nuclear literature, and it is not in UniProt's SUBUNIT block. Reason: Removed because GO:0005515 carries no functional information, not because the SH2D4A interaction is false - the HuRI identification is reproducible and is retained in IntAct and in UniProt's INTERACTION block, where it belongs. MODIFY is not available here: the screen is an all-by-all two-hybrid assay with no functional follow-up on this pair, so there is no evidence-supported molecular function to replace the term with, and inventing one from interaction evidence alone is exactly what the policy forbids. The contrast is instructive: the partners that do carry mechanism - endophilin 2/3, dynamin 2, CaMKIIbeta, PSEN1 - sit in UniProt's SUBUNIT block only as 'By similarity' and have no human IPI row at all, so the human interaction record for this gene is inverted with respect to biological importance. The informative molecular function the record was missing is added separately as GO:0030674 protein-macromolecule adaptor activity, on the characterised partners rather than on these four. Supporting Evidence: file:human/ARC/ARC-uniprot.txt Q7LC44; Q9H788: SH2D4A; NbExp=3; file:human/ARC/ARC-uniprot.txt SUBUNIT: Homooligomer; homooligomerizes into virion-like capsids |
| GO:0005737 cytoplasm | IDA PMID:21834987 Identification and characterization of a set of conserved an... | KEEP AS NON CORE | Summary: GFP-ARC transfected into PC3 prostate carcinoma cells gave diffuse cytoplasmic fluorescence with some plasma-membrane enrichment. Arc is certainly a cytoplasmic protein, so the call is not wrong, but the evidence behind it is ectopic overexpression of a tagged construct in a cell type that does not express ARC. Reason: True but uninformative: GO:0005737 is the parent of every location that actually characterises this protein (postsynaptic density, dendritic spine, early endosome membrane, virus-like capsid). Worth noting that this paper carries a 2024 author correction about its ARC panels - the duplicated images are in the HeLa knockdown figure rather than the localisation figure, and the authors state the conclusions are unaffected, but it is a data-integrity event on this gene. Supporting Evidence: PMID:21834987 GFP-ARC, FAM40A, FAM40B and FMNL3 proteins showed cytoplasmic localization with some enrichment on the plasma membrane compared to GFP alone (Figure 8B). PMID:39390519 The images for siARC were incorrect and were the same as the siZRANB images. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9031624 | KEEP AS NON CORE | Summary: Compartment assignment attached to the Reactome 'ARC gene expression' pathway, which places the newly translated ARC protein in the cytosol. Uncontroversial - Arc is translated on cytosolic and dendritic ribosomes and has no signal peptide or transmembrane segment - but it is a pathway-diagram statement rather than an observation. Reason: Correct and generic. Arc does reach membranes, but by palmitoylation from the cytosolic face rather than by co-translational insertion, so cytosol is the right default compartment. It carries no information about what Arc does. Supporting Evidence: PMID:29264923 In this study, we show that Arc associates with pure phospholipid vesicles in vitro and undergoes palmitoylation in neurons, a modification that allows it to insert directly into the hydrophobic core of the bilayer. |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The protein is named for a cytoskeletal association, and the association is real - Lyford et al. showed rat Arc co-precipitates with F-actin and co-localises with the actin matrix - but the specific provenance of this IEA is weak. UniProt records 'Cytoplasm, cytoskeleton {ECO:0000269|PubMed:21834987}', citing Bai et al., and what Bai et al. actually show is that GFP-ARC is diffusely cytoplasmic with plasma-membrane enrichment, plus an actin-bundling phenotype on knockdown. A phenotype is not a localisation, so the cited anchor does not support the keyword it is attached to. Reason: Kept because the biology is right on independent rodent evidence, not because the cited chain is sound. Downgraded to non-core because Arc's cytoskeletal link is indirect and regulatory - it controls local actin polymerisation during LTP consolidation rather than being a structural cytoskeletal component - and because the modern mechanistic account of the protein is Gag-like capsid assembly and endocytic adaptation, not cytoskeletal architecture. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB-SubCell:SL-0090 · UniProt SubCell keyword SL-0090, Cytoskeleton SOURCE WEAK OR INFERRED The SubCell keyword Cytoskeleton is the proximate source. On the human record it is anchored to ECO:0000269|PubMed:21834987, but that paper reports a diffuse cytoplasmic GFP-ARC distribution and an actin-bundling knockdown phenotype in PC3 and HeLa cells, not cytoskeletal localisation of ARC. The genuine support for the keyword is rodent (PMID:7857651), which is not the citation UniProt carries. Supporting Evidence: PMID:7857651 Analysis of the deduced amino acid sequence indicates a region of homology with alpha-spectrin, and the full-length protein, prepared by in vitro transcription/translation, coprecipitates with F-actin. PMID:21834987 ARC depletion led to a strong increase in thick actin filament bundles at the edges of cells, and in some cells to an increase in stress fibres, similar to the response of PC3 cells. PMID:17898216 Thus, Arc couples two central tenets of LTP consolidation: activity-induced gene expression and regulation of local actin polymerization. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The best-supported of the six IBAs. Three gene-level donors - mouse Arc, rat Arc and human ARC - and the rat evidence is immunogold EM in adult hippocampus placing Arc at or very near the postsynaptic plasma membrane. The mechanism is known: Arc is palmitoylated on the 94-CLCRC-98 cysteine cluster, which inserts it directly into the bilayer, and UniProt accordingly annotates the human protein as a lipid-anchored postsynaptic cell membrane protein. Reason: Correctly placed node, three independent donors, a known membrane-attachment mechanism, and an is_active_in qualifier that matches where the endocytic work happens. Core: the plasma membrane is where Arc recruits endophilin and dynamin to internalise AMPA receptors. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:88067 · Arc (Mus musculus), = UniProtKB:Q9WV31 SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an EXP annotation on PMID:22036569, where Arc is characterised as a postsynaptic protein recruiting endophilin2/3 and dynamin to endosomes that traffic AMPA receptors. PANTHER:PTN008562333 · PTHR15962 Arc IBD node, placed at Tetrapoda (taxon:32523) SUPPORTS TRANSFER Sole IBD node of PTHR15962, placed at Tetrapoda (taxon:32523). Its plasma membrane assertion is seeded by mouse Arc, rat Arc and human ARC itself - three gene-level donors, the largest seed set of the six. Human ARC is a tetrapod Arc and sits inside the inheriting clade. The node deliberately excludes Drosophila Arc1 (Q7K1U0), which PANTHER places in the same family and subfamily but which is an independent Ty3/gypsy domestication; QuickGO confirms dArc1 carries no IBA from this node. RGD:62037 · Arc (Rattus norvegicus), = UniProtKB:Q63053 SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is SynGO IDA and IMP annotations on PMID:17088211, including the immunogold EM that puts Arc at or very near the postsynaptic plasma membrane. UniProtKB:Q7LC44 · ARC (Homo sapiens), the target itself SUPPORTS TRANSFER The target's own IDA (PMID:21834987) is one of the descendant evidences behind the IBD, which is expected rather than circular. It is also the weakest of the three donors, being GFP-ARC overexpressed in PC3 cells; the mouse and rat donors carry the argument. Supporting Evidence: PMID:17088211 Arc immuno-EM gold particles were present throughout the spine but were enriched over the postsynaptic density (PSD) where they appeared at, or very near, the plasma membrane PMID:29264923 We further show that Arc can be palmitoylated on cysteines clustered in a motif, 94CLCRC98. file:human/ARC/ARC-uniprot.txt PTM: Palmitoylation anchors the protein into the membrane by allowing |
| GO:0005886 plasma membrane | IDA PMID:21834987 Identification and characterization of a set of conserved an... | ACCEPT | Summary: GFP-ARC in PC3 cells showed 'some enrichment on the plasma membrane compared to GFP alone'. The conclusion is right for the wrong reasons: Arc genuinely is a membrane-associated protein, but it gets there by palmitoylation in neurons, and a hedged enrichment of an overexpressed GFP fusion in a prostate carcinoma line is not that observation. Reason: The term is right and core - Arc acts at the postsynaptic plasma membrane, anchored by palmitoylation - so this row is accepted alongside the IBA rather than graded down for a term the same record already carries as core. The evidence behind this particular row is nonetheless the weakest of the three routes to it: ectopic expression in a non-expressing carcinoma line, with a GFP tag at the N-terminus adjacent to the palmitoylation motif, and a hedged 'some enrichment' description. The mouse and rat donors of the IBA carry the claim. The paper's 2024 author correction concerns its ARC knockdown panels rather than this figure. Supporting Evidence: PMID:21834987 GFP-ARC, FAM40A, FAM40B and FMNL3 proteins showed cytoplasmic localization with some enrichment on the plasma membrane compared to GFP alone (Figure 8B). PMID:39390519 Following publication of the original article, [1], the authors noticed that Fig. 6 contained an error. |
| GO:0005938 cell cortex | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The original Arc paper localised the native protein to the subplasmalemmal cortex of neuronal cell bodies and dendrites, co-localising with the actin matrix. UniProt carries this on the human entry as 'Cytoplasm, cell cortex {ECO:0000250|UniProtKB:Q63053}' with the note 'Associated with the cell cortex of neuronal soma and dendrites (By similarity)'. Reason: Well-founded on rat evidence and coherent with the palmitoyl anchor, but it is a description of where the diffuse somatodendritic pool sits rather than of where Arc acts. The functionally informative locations are the postsynaptic density, the dendritic spine and the early endosome. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0138 · UniProt SubCell keyword SL-0138, Cell cortex SUPPORTS TRANSFER The SubCell keyword Cell cortex is the proximate source of this IEA. Unlike the Cytoskeleton keyword on this same record, this one is correctly anchored: its human entry carries ECO:0000250|UniProtKB:Q63053 and the rat observation it derives from (PMID:7857651) is explicitly a subplasmalemmal-cortex localisation of the native protein. Supporting Evidence: PMID:7857651 Confocal microscopy of the native protein in hippocampal neurons demonstrates that the IEG-encoded protein is enriched in the subplasmalemmal cortex of the cell body and dendrites and thus colocalizes with the actin cytoskeletal matrix. file:human/ARC/ARC-uniprot.txt prevent their undesired enhancement. Associated with the cell cortex of |
| GO:0007616 long-term memory | IEA GO_REF:0000107 | ACCEPT | Summary: Compara projection from mouse Arc, whose long-term memory annotation is an IMP on Zhang et al. 2019. The claim is one of the most robust in the field: Arc-null mice form normal short-term but no long-lasting memories across both implicit and explicit tasks, and antisense knockdown in rat hippocampus blocks consolidation without affecting acquisition. Reason: Core biological role, supported by loss-of-function in two species and by a targeted knock-in that removes only the CaMKII phosphosites. Nothing about it is human-specific, but nothing suggests the human orthologue differs either. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IMP annotation on PMID:31151856; the Arc-null phenotype in PMID:17088210 is the broader context. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. Supporting Evidence: PMID:17088210 These animals fail to form long-lasting memories for implicit and explicit learning tasks, despite intact short-term memory. PMID:10818134 Our studies show that disruption of Arc protein expression impairs the maintenance phase of LTP without affecting its induction and impairs consolidation of LTM for spatial water task training without affecting task acquisition or short-term memory. |
| GO:0007616 long-term memory | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from rat Arc, whose IMP rests on Guzowski et al. 2000: intrahippocampal antisense oligodeoxynucleotides against Arc impaired consolidation of long-term memory for the spatial water task while leaving acquisition and short-term memory intact. Reason: A clean loss-of-function result with the right internal control - the dissociation between acquisition and consolidation is what makes it informative rather than merely a deficit. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IMP annotation on PMID:10818134, an antisense knockdown study in hippocampus. Supporting Evidence: PMID:10818134 We used intrahippocampal infusions of antisense oligodeoxynucleotides to inhibit Arc protein expression and examined the effect of this treatment on both LTP and spatial learning. PMID:10818134 Thus, Arc appears to play a fundamental role in the stabilization of activity-dependent hippocampal plasticity. |
| GO:0007616 long-term memory | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from mouse Arc, whose IMP is on Zhang et al. 2019, the knock-in model in which the CaMKII phosphorylation sites of the Gag domain are mutated. Same term as the rat-donor row, reached from a different and mechanistically sharper experiment. Reason: Two donors, two species, two independent perturbation designs. The knock-in is the more informative of the two because it isolates the oligomerisation switch rather than removing the protein. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IMP annotation on PMID:31151856, a CaMKII-phosphosite knock-in model. Supporting Evidence: PMID:31151856 CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. PMID:31151856 These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory. |
| GO:0007616 long-term memory | TAS PMID:15537891 Synaptic targeting by Alzheimer's-related amyloid beta oligo... | ACCEPT | Summary: A traceable author statement in an amyloid-beta oligomer paper, citing Guzowski et al. 2000 for the claim that appropriate Arc expression is essential for LTP and long-term memory formation. The statement is accurate and the primary source is in this file, annotated independently. Reason: The term is right and core. The evidence code is the weakest usable one and the citation is second-hand, but the annotation is not doing any work the ISS and IEA rows are not already doing better. Worth recording that this reference is not a mass projection: paginating QuickGO by reference=PMID:15537891 returns 16 annotations across only four distinct entities (human ARC, rat Arc and two ComplexPortal complexes), so its four ARUK-UCL TAS rows are gene-specific rather than boilerplate. Supporting Evidence: PMID:15537891 Animal model studies have shown that appropriate Arc expression is essential for LTP and long-term memory formation ( Guzowski et al., 2000 ). |
| GO:0014069 postsynaptic density | IEA GO_REF:0000044 | ACCEPT | Summary: SubCell keyword mapping for a location established by immunogold EM in adult rat hippocampus: Arc gold particles are enriched over the PSD and at its lateral margins, which is precisely where AMPA receptors diffuse out and are endocytosed. UniProt's note says 'Enriched in postsynaptic density of dendritic spines'. Reason: One of the two or three locations that actually explain what Arc does. The PSD and its lateral margin are the site of the endophilin/dynamin-dependent AMPAR removal that Arc drives. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0297 · UniProt SubCell keyword SL-0297, Postsynaptic density SUPPORTS TRANSFER The SubCell keyword Postsynaptic density is the proximate source of this IEA. Its human entry carries ECO:0000250|UniProtKB:Q63053, and the rat annotation behind it is SynGO's set of IDA/IMP rows on PMID:17088211 - immunogold EM plus functional perturbation, not a statement. Supporting Evidence: PMID:17088211 Arc immuno-EM gold particles were present throughout the spine but were enriched over the postsynaptic density (PSD) where they appeared at, or very near, the plasma membrane PMID:17088211 We find that immunogold EM labeling of endophilins 2/3 and Arc occurs at the lateral margins of spines and near the PSD, precisely where AMPARs diffuse out of the PSD and are endocytosed. file:human/ARC/ARC-uniprot.txt Enriched in postsynaptic density of dendritic spines. Targeted to |
| GO:0014069 postsynaptic density | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer from rat Arc, whose PSD annotation rests on SynGO IDA and IMP rows on Chowdhury et al. 2006 and an additional UniProt EXP row on the same paper. Arc is also actively targeted there: Okuno et al. showed that CaMKIIbeta not bound to calmodulin recruits Arc specifically to inactive synapses, an 'inverse synaptic tagging' mechanism. Reason: Strong donor evidence, a known targeting mechanism, and a location that carries the mechanism. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is a set of SynGO IDA and IMP annotations plus a UniProt EXP annotation, all on PMID:17088211. Supporting Evidence: PMID:17088211 Arc immuno-EM gold particles were present throughout the spine but were enriched over the postsynaptic density (PSD) where they appeared at, or very near, the plasma membrane PMID:22579289 Here, we show targeting of Arc to inactive synapses via a high-affinity interaction with CaMKIIbeta that is not bound to calmodulin. |
| GO:0030425 dendrite | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automatic pipeline: Ensembl Compara projection from mouse Arc plus the UniProt SubCell Dendrite keyword. Dendritic enrichment of both Arc mRNA and Arc protein is one of the oldest and most reproduced facts about this gene - it is in the title of the founding paper - and mouse Arc carries IDA annotations for it on two separate studies. Reason: Three concordant routes to a location that is not in serious doubt, and it is where the protein does its synaptic work. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is IDA annotations on PMID:23936366 and PMID:31151856. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. UniProtKB-SubCell:SL-0283 · UniProt SubCell keyword SL-0283, Dendrite SUPPORTS TRANSFER The SubCell keyword Dendrite is the third leg of this combined IEA. Its human entry carries ECO:0000250|UniProtKB:Q63053, tracing to the rat literature that first described dendritic enrichment of Arc (PMID:7857651). Supporting Evidence: PMID:7857651 Both the mRNA and the encoded protein are enriched in neuronal dendrites. PMID:17088211 Consistent with EM localizations, Arc protein localized in DIV 21 hippocampal primary neurons to dendrites with puncta in spines, and colocalized with both the AMPAR subunit GluR1 and endophilin 3 ( Figures 2C ). |
| GO:0030665 clathrin-coated vesicle membrane | IEA GO_REF:0000044 | MODIFY | Summary: UniProt records 'Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000269|PubMed:24945773}', and the SubCell mapping turns that into GO:0030665. But the cited paper reports association with clathrin-coated PITS, not with the membrane of budded clathrin-coated vesicles: Mabb et al. used TIRF microscopy and described a pool of Arc at CCPs, with the association explicitly transient and compared to the CCP dynamics of endophilin-3 and dynamin-2. The distinction is not pedantic - GO:0005905 is defined as the invagination on which a clathrin coat forms and which can then be converted by budding into a vesicle, whereas GO:0030665 is the lipid bilayer of the vesicle that has already budded. A protein that arrives before scission and departs with uncoating is at the pit. Reason: The evidence of record supports the sibling term. Mabb et al. also observed a large fraction of Arc surface events that did not co-localise with CCPs at all, and suggested Arc may act in clathrin-independent, dynamin-dependent endocytosis, which argues further against committing Arc to the coated vesicle itself. GO:0005905 resolves and sits under the endomembrane system, so the replacement is well-formed. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB-SubCell:SL-0071 · UniProt SubCell keyword SL-0071, Clathrin-coated vesicle membrane SUPPORTS SOURCE BUT NOT TARGET The SubCell keyword Clathrin-coated vesicle membrane is the proximate source, anchored to ECO:0000269|PubMed:24945773. The citation is correct and the compartment family is right, but the paper's observation is pit association, not coated-vesicle membrane residence, so the keyword - and the GO term it maps to - overshoots by one step along the endocytic pathway. Proposed replacements: clathrin-coated pit Supporting Evidence: PMID:24945773 Using TIRF microscopy, we found that a pool of Arc localizes to CCPs in COS7 cells. PMID:24945773 The transient association of Arc with clathrin-coated pits (CCPs) is similar to the reported dynamics of its interacting partners, endophilin-3 and dynamin-2 (Perrais and Merrifield, 2005). PMID:24945773 We observed a large fraction of Arc events at the cell surface that did not colocalize with CCPs but did colocalize with Triad3A, suggesting that Arc may also function in dynamin-dependent but clathrin-independent pathways to regulate endocytosis (Hansen and Nichols, 2009). |
| GO:0031901 early endosome membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Arc, endophilin and dynamin form a cooperative assembly on early endosomes: Arc-endophilin vesicles co-localise with transferrin receptor and with endocytosed transferrin, but not with LAMP1. Wu et al. went on to show that the same Arc-endosome traffics APP and BACE1 and that Arc associates with presenilin-1 there. Reason: A mechanistically load-bearing location: it is where the internalised AMPA receptors go and where Arc's endocytic partners work. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0093 · UniProt SubCell keyword SL-0093, Early endosome membrane SUPPORTS TRANSFER The SubCell keyword Early endosome membrane is the proximate source of this IEA. Its human entry carries ECO:0000250|UniProtKB:Q63053, and rat Arc's own annotation for GO:0031901 is a UniProt EXP row on PMID:17088211, the paper that established the Arc-endophilin-dynamin endosome. Supporting Evidence: PMID:17088211 Arc-endophilin vesicles co-localized with endogenous transferrin receptors, a marker for early endosomes, but not LAMP1, a lysosomal marker (Supplemental Figure S2A). PMID:22036569 Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both hebbian and non-hebbian forms of plasticity. |
| GO:0031901 early endosome membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Curator transfer from rat Arc, whose annotation for this term is a UniProt EXP row on Chowdhury et al. 2006. The two routes - SubCell keyword and explicit ISS - reach the same term from the same underlying experiment. Reason: Sound donor and a location that carries mechanism rather than just describing residence. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is a UniProt EXP annotation on PMID:17088211. Supporting Evidence: PMID:17088211 These data suggest that Arc-endophilin-dynamin vesicles are predominantly early endosomes in HeLa cells. PMID:17088211 Arc-endophilin vesicles also co-localized with endocytosed transferrin ( Figure 5C ), further suggesting that these are trafficking endosomes. |
| GO:0043025 neuronal cell body | TAS PMID:15537891 Synaptic targeting by Alzheimer's-related amyloid beta oligo... | KEEP AS NON CORE | Summary: A traceable author statement in an amyloid-beta oligomer paper, restating Steward and Worley's finding that constitutively expressed Arc sits in cell bodies rather than at synapses. The statement is made in order to argue that the ADDL-induced dendritic Arc the authors see is ectopic. Reason: The location is real and independently supported - Lyford et al. describe cortical enrichment in the cell body, and Okuno et al. describe activity-induced Arc being redistributed from the soma to individual synapses - but somatic residence is the resting state of a protein whose function is executed in dendrites and spines. TAS is also the weakest usable code here. Peripheral. Supporting Evidence: PMID:15537891 This location appears to be an ectopic induction, because low levels of Arc protein that are expressed constitutively are known to localize in cell bodies and not at synapses ( Steward and Worley, 2001 ). PMID:7857651 Confocal microscopy of the native protein in hippocampal neurons demonstrates that the IEG-encoded protein is enriched in the subplasmalemmal cortex of the cell body and dendrites and thus colocalizes with the actin cytoskeletal matrix. |
| GO:0043197 dendritic spine | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automatic pipeline reaching a location established by immunogold EM (gold particles throughout the spine, enriched over the PSD), by light microscopy in cultured hippocampal neurons, and by mouse IDA on PMID:31151856. Reason: The spine is where Arc's synaptic function is executed. Three concordant routes, none of them in tension with the others. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:31151856. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. UniProtKB-SubCell:SL-0284 · UniProt SubCell keyword SL-0284, Dendritic spine SUPPORTS TRANSFER The SubCell keyword Dendritic spine is the third leg of this combined IEA. Its human entry carries ECO:0000250|UniProtKB:Q63053; the rat evidence is the immunogold EM of PMID:17088211. Supporting Evidence: PMID:17088211 When Arc was expressed individually, the transgene accumulates in dendrites with a uniform, dispersed distribution, and shows enrichment in dendritic spines (Supplemental Figure S4A). file:human/ARC/ARC-uniprot.txt Enriched in postsynaptic density of dendritic spines. Targeted to |
| GO:0043197 dendritic spine | ISS GO_REF:0000024 | ACCEPT | Summary: Explicit curator transfer from mouse Arc, whose spine annotation is an IDA on Zhang et al. 2019. Duplicates the automatic route above by a different method, which is fine and expected. Reason: Sound donor, sound transfer, core location. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:31151856. Supporting Evidence: PMID:31151856 Arc is a synaptic protein essential for memory consolidation. PMID:17088211 When Arc was expressed individually, the transgene accumulates in dendrites with a uniform, dispersed distribution, and shows enrichment in dendritic spines (Supplemental Figure S4A). |
| GO:0045121 membrane raft | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection from mouse Arc, whose raft annotation is an IDA on Barylko et al. 2018. That paper found roughly half of the detergent-insoluble synaptosomal Arc in raft fractions and explained it mechanistically: Arc is palmitoylated on the 94-CLCRC-98 cysteine cluster, and rafts are enriched in palmitoylated proteins. Reason: Real, mechanistically explained, and functionally relevant - the same cysteine mutations that block palmitoylation abolish an Arc-dependent form of synaptic depression. But it is a sub-domain refinement of the postsynaptic membrane pool rather than a distinct site of action, and it rests on biochemical fractionation. Peripheral. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29264923, a palmitoylation and membrane-binding study. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. Supporting Evidence: PMID:29264923 We confirmed that ~50% of synaptosomal Arc that is not extracted by cold Triton X-100 associates with membrane rafts (Figure 1C). PMID:29264923 Lastly, we demonstrate that mutation of these cysteines abolishes an Arc-dependent form of synaptic depression, pointing to a functional role for Arc palmitoylation in neurons. |
| GO:0045121 membrane raft | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator transfer of the same mouse observation by the explicit ISS route. The palmitoylation motif 94-CLCRC-98 is present unchanged in the human sequence, so the structural basis for raft partitioning transfers with the sequence. Reason: Same judgement as the Compara row: correct, mechanistically grounded, but a membrane sub-domain rather than a site of action. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29264923. Supporting Evidence: PMID:29264923 The palmitoylated cysteines are clustered in a motif, 94CLCRC98, located in the N-terminal half of the protein, which has not yet been structurally characterized. file:human/ARC/ARC-uniprot.txt PTM: Palmitoylation anchors the protein into the membrane by allowing |
| GO:0045202 synapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: SubCell keyword mapping. Synaptic localisation of Arc is about as well established as anything in this record - rat Arc alone carries over a dozen experimental rows for this term from SynGO and UniProt across PMID:17088211, PMID:17898216 and PMID:22579289. Reason: Correct but strictly less informative than the postsynaptic density, postsynaptic membrane, dendritic spine and glutamatergic synapse rows that the same record already carries. Retained as the parent. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0258 · UniProt SubCell keyword SL-0258, Synapse SUPPORTS TRANSFER The SubCell keyword Synapse is the proximate source of this IEA. Its human entry carries ECO:0000250|UniProtKB:Q63053, and rat Arc's own record for GO:0045202 holds SynGO IDA/IMP rows on PMID:17088211 and PMID:17898216 plus a UniProt EXP row on PMID:22579289. The transfer is sound; only the term's granularity is unremarkable. Supporting Evidence: PMID:17088211 Consistent with EM localizations, Arc protein localized in DIV 21 hippocampal primary neurons to dendrites with puncta in spines, and colocalized with both the AMPAR subunit GluR1 and endophilin 3 ( Figures 2C ). PMID:22579289 Synaptic Arc accumulates in inactive synapses that previously experienced strong activation and correlates with removal of surface GluA1 from individual synapses. |
| GO:0045202 synapse | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Explicit curator transfer of the same fact from rat Arc, which carries the densest experimental support for this term of any donor in this file. Reason: Correct, extremely well supported, and a generic parent of the informative synaptic terms. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is a large set of SynGO IDA/IMP rows on PMID:17088211 and PMID:17898216 plus a UniProt EXP row on PMID:22579289. Supporting Evidence: PMID:17898216 In addition to de novo gene expression, recent work suggests that LTP consolidation requires actin polymerization-dependent expansion of the postsynaptic density (PSD) and dendritic spine ( Fukazawa et al., 2003 ; Matsuzaki et al., 2004 ; Zito et al., 2004 ). PMID:22579289 Synaptic Arc accumulates in inactive synapses that previously experienced strong activation and correlates with removal of surface GluA1 from individual synapses. |
| GO:0045211 postsynaptic membrane | IEA GO_REF:0000044 | ACCEPT | Summary: SubCell keyword Postsynaptic cell membrane, which UniProt qualifies as a lipid anchor. This is the specific membrane at which Arc recruits endophilin and dynamin to remove AMPA receptors, and the anchoring mechanism is palmitoylation rather than a transmembrane segment - consistent with the sequence, which has no TM region. Reason: A location that is inseparable from the function. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0219 · UniProt SubCell keyword SL-0219, Postsynaptic cell membrane SUPPORTS TRANSFER The SubCell keyword Postsynaptic cell membrane is the proximate source of this IEA. Its human entry carries ECO:0000250|UniProtKB:Q9WV31 with a Lipid-anchor qualifier; mouse Arc's own GO:0045211 row is a UniProt EXP annotation on PMID:22036569. Supporting Evidence: file:human/ARC/ARC-uniprot.txt {ECO:0000250|UniProtKB:Q9WV31}. Postsynaptic cell membrane PMID:17088211 Here, we demonstrate that Arc plays a regulatory role in AMPAR trafficking via its interaction with components of the endocytic machinery, endophilin and dynamin. |
| GO:0045211 postsynaptic membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Explicit transfer from mouse Arc, whose postsynaptic membrane annotation is a UniProt EXP row on Wu et al. 2011 - the study that characterised Arc as a postsynaptic protein recruiting endophilin2/3 and dynamin to endosomes trafficking AMPA receptors. Reason: Sound donor and a location that carries the mechanism. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is a UniProt EXP annotation on PMID:22036569. Supporting Evidence: PMID:22036569 Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both hebbian and non-hebbian forms of plasticity. |
| GO:0048168 regulation of neuronal synaptic plasticity | IBA GO_REF:0000033 | ACCEPT | Summary: The oldest of the six node assertions (2017) and the one with the weakest recorded seed. Its single gene-level donor is rat Arc, whose evidence is an RGD IEP on Lyford et al. 1995 - the discovery paper, which showed activity-dependent induction and dendritic enrichment and drew a hedged conclusion. An expression-pattern code is thin support for an involved_in process annotation. What rescues it is that the claim has since been established directly, by antisense knockdown in rat, by germline knockout in mouse, by acute knockdown in Purkinje cells and by a phosphosite knock-in - none of which is in the WITH/FROM, because the IBD predates most of it. Reason: No failure: the node is correctly placed, human ARC is inside the inheriting clade, and the term is right and core. The seed is simply the historically first evidence rather than the best available, which is a property of when the IBD was made rather than a defect in the inference. Recorded on the donor entry rather than converted into a failure mode the biology does not support. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008562333 · PTHR15962 Arc IBD node, placed at Tetrapoda (taxon:32523) SUPPORTS TRANSFER Sole IBD node of PTHR15962, placed at Tetrapoda (taxon:32523). Its regulation of neuronal synaptic plasticity assertion is seeded by a single gene-level donor, rat Arc. Human ARC is a tetrapod Arc and sits inside the inheriting clade. The node deliberately excludes Drosophila Arc1 (Q7K1U0), which PANTHER places in the same family and subfamily but which is an independent Ty3/gypsy domestication; QuickGO confirms dArc1 carries no IBA from this node. Dated 20170906, the oldest of the six assertions. Note that dArc1 carries its own IDA for this same term (UniProt, PMID:29328915) and receives no IBA from this node, so the fly's independently evolved plasticity role is correctly kept out of the tetrapod inference. RGD:62037 · Arc (Rattus norvegicus), = UniProtKB:Q63053 SOURCE WEAK OR INFERRED Rat Arc's only annotation for GO:0048168 is an RGD IEP on PMID:7857651, an expression-pattern code on the 1995 discovery paper whose own conclusion is hedged. The donor is the right gene and the right term, but the recorded evidence is the weakest of any seed in this family; the claim's real support (PMID:10818134, PMID:17088210, PMID:17088213, PMID:31151856) sits outside this WITH/FROM. Supporting Evidence: PMID:7857651 Our observations suggest that Arc may play a role in activity-dependent plasticity of dendrites. PMID:17088213 Conversely, loss of Arc results in increased AMPAR function and abolishes homeostatic scaling of AMPARs. PMID:17088210 Together, these results demonstrate a critical role for Arc/Arg3.1 in the consolidation of enduring synaptic plasticity and memory storage. |
| GO:0050804 modulation of chemical synaptic transmission | IEA GO_REF:0000120 | ACCEPT | Summary: Three-source combined automatic annotation: Compara projection from mouse Arc, and the InterPro Arc family signature. Mouse Arc's own evidence is two IMP rows on PMID:31151856 plus an IDA on PMID:29264923. Arc modulates transmission by setting the number of surface AMPA receptors, which is as direct a form of modulation as exists. Reason: Correct, well sourced, and the GO term sits at a sensible level: it is the parent under which the LTP, LTD and homeostatic-scaling regulation terms all live, and Arc participates in all three. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is two IMP annotations on PMID:31151856 and an IDA on PMID:29264923. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. InterPro:IPR023263 · InterPro IPR023263, Activity-regulated cytoskeleton-associated protein (family) SUPPORTS TRANSFER IPR023263 is the single-member Arc family signature rather than a broad Gag superfamily signature, so an InterPro2GO rule attached to it asserts of Arc what was shown for Arc. Supporting Evidence: PMID:17088213 Here, we demonstrate that Arc/Arg3.1, an immediate-early gene (IEG) that is rapidly induced by neuronal activity associated with information encoding in the brain, mediates homeostatic synaptic scaling of AMPA type glutamate receptors (AMPARs) via its ability to activate a novel and selective AMPAR endocytic pathway. PMID:29264923 Lastly, we demonstrate that mutation of these cysteines abolishes an Arc-dependent form of synaptic depression, pointing to a functional role for Arc palmitoylation in neurons. |
| GO:0050804 modulation of chemical synaptic transmission | ISS GO_REF:0000024 | ACCEPT | Summary: Explicit curator transfer of the same mouse evidence. The mechanism behind it is specific: Arc accumulates at synapses that have gone quiet after strong activation, bound by CaMKIIbeta in its calmodulin-free state, and strips surface GluA1 from them. Reason: Sound donor, sound transfer, and the process is central to what Arc does. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is two IMP annotations on PMID:31151856 and an IDA on PMID:29264923. Supporting Evidence: PMID:22579289 A lack of CaMKIIbeta either in vitro or in vivo resulted in loss of Arc upregulation in the silenced synapses. PMID:31151856 We generated a mouse genetic model expressing mutant Arc that cannot be phosphorylated by CaMKII and found that baseline synaptic transmission and LTP in the hippocampus appear normal but metabotropic receptor-LTD is increased in magnitude. |
| GO:0051028 mRNA transport | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from rat Arc, whose annotation is an IDA on Pastuzyn et al. 2018. The transport here is of an unusual kind - Arc capsids carry Arc mRNA out of one neuron in extracellular vesicles and deliver it into the cytoplasm of another, where it can be translated on demand - but GO:0051028 explicitly covers movement of mRNA 'into, out of or within a cell, or between cells', so the term fits without strain. Reason: Core. Together with GO:0110077 this is the process the capsid exists to perform, and the definition of GO:0051028 was written broadly enough to admit it. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29328916, which showed capsid-mediated delivery of Arc mRNA into Arc-null recipient neurons. Supporting Evidence: PMID:29328916 To test whether Arc capsids can transfer Arc mRNA into neurons, we incubated cultured hippocampal neurons from Arc KO mice with prArc. PMID:29328916 RNase treatment of prArc prior to incubation had no effect on mRNA transfer (Figure S5A), further suggesting that Arc capsids are able to protect and encapsulate Arc mRNA. |
| GO:0051260 protein homooligomerization | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from rat Arc's IDA on Pastuzyn et al. 2018, but unusually for this file the human protein has direct evidence of its own that GOA does not use: Myrum et al. expressed and purified recombinant human Arc and showed by DLS, AFM and EM that it reversibly self-associates into large soluble oligomers. Eriksen et al. then localised the responsible interface to a 7-residue motif in the N-terminal coil and solved it at 0.95 A on the human sequence. Reason: Core, and the ISS understates the evidence - the oligomerisation of the human protein has been measured directly. It is also the step that everything else depends on: the same motif is required for capsid formation, for mRNA-induced higher-order assembly and for Arc-facilitated endocytosis, and CaMKII phosphorylation of the Gag N-lobe switches it off. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29328916. The transfer is sound, but it is also redundant: human Arc's self-association was measured directly on purified recombinant hArc in PMID:25748042, which GOA does not cite. Supporting Evidence: PMID:25748042 hArc appears to be pyramid-shaped as a monomer and is capable of reversible self-association, forming large soluble oligomers. PMID:33175445 Within this region, we identified a 7-residue oligomerization motif, critical for the formation of virus-like capsids. file:human/ARC/ARC-uniprot.txt SUBUNIT: Homooligomer; homooligomerizes into virion-like capsids |
| GO:0060291 long-term synaptic potentiation | TAS PMID:15537891 Synaptic targeting by Alzheimer's-related amyloid beta oligo... | ACCEPT | Summary: Traceable author statement citing Guzowski et al. 2000. The underlying result is that blocking Arc expression leaves LTP induction intact but abolishes its maintenance - Arc is required for the late, protein-synthesis-dependent phase. Messaoudi et al. later showed the same thing in vivo with a mechanism attached, via local actin polymerisation in the dentate gyrus. Reason: Correct and core. Arc is not a component of LTP induction machinery but it is a required participant in the process as a whole, which is what involved_in asserts. The Arc-null mouse phenotype is biphasic - enhanced early phase, absent late phase - which is a stronger statement about participation than a simple deficit would be. Supporting Evidence: PMID:15537891 Animal model studies have shown that appropriate Arc expression is essential for LTP and long-term memory formation ( Guzowski et al., 2000 ). PMID:17088210 Moreover, they exhibit a biphasic alteration of hippocampal long-term potentiation in the dentate gyrus and area CA1 with an enhanced early and absent late phase. PMID:17898216 These results indicate that Arc synthesis at 2 h is critical for LTP consolidation. |
| GO:0060997 dendritic spine morphogenesis | TAS PMID:15537891 Synaptic targeting by Alzheimer's-related amyloid beta oligo... | MARK AS OVER ANNOTATED | Summary: The cited statement is doubly hedged and second-hand: Lacor et al. write that Arc 'is coupled to F-actin and linked functionally to spine morphology, and its chronic overexpression has been suggested to generate abnormal spine structure', citing Kelly and Deadwyler. The paper's own spine observation is that spines in amyloid-beta-oligomer-treated cultures - where Arc is ectopically induced fivefold - are longer and more protruded than controls. A spine-shape abnormality under pathological ectopic induction is not evidence that Arc executes spine morphogenesis. Reason: Not wrong in spirit - Arc does influence spine structure through local actin regulation during LTP consolidation - but involved_in GO:0060997 claims participation in the morphogenetic process itself, which no experiment in this reference supports. The defensible version of the claim is already on the gene as GO:0061001 regulation of dendritic spine morphogenesis, so nothing is lost by marking this one down rather than proposing a replacement that duplicates an existing row. Supporting Evidence: PMID:15537891 Arc protein is coupled to F-actin and linked functionally to spine morphology, and its chronic overexpression has been suggested to generate abnormal spine structure ( Kelly and Deadwyler, 2003 ). PMID:15537891 The ADDL-induced increase in Arc was fivefold over vehicle-treated cultures. |
| GO:0061001 regulation of dendritic spine morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ARUK-UCL transfer from rat Arc, whose own annotation for this term is an IGI on the same Lacor et al. paper. The regulation-of formulation is the defensible one: Arc controls local actin polymerisation at potentiated synapses, and spine and PSD expansion follow from that, rather than Arc being part of the morphogenetic machinery. Reason: Real but indirect and downstream. The mechanism that supports it - regulation of local actin polymerisation during LTP consolidation - is well demonstrated in vivo, but spine remodelling is a consequence of Arc's synaptic activity rather than one of its functions. Peripheral. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SOURCE WEAK OR INFERRED Rat Arc's GO:0061001 row is an ARUK-UCL IGI on PMID:15537891, an amyloid-beta oligomer study in which Arc is ectopically induced rather than manipulated, so the donor evidence is context-specific. The regulation-of term survives because the independent in vivo evidence (PMID:17898216) supports it; the donor row alone would not carry it. Supporting Evidence: PMID:17898216 Thus, Arc couples two central tenets of LTP consolidation: activity-induced gene expression and regulation of local actin polymerization. PMID:15537891 Examination of spine morphology in the current experiments indicated that Arc-positive spines in oligomer-treated groups differed from the few Arc-positive spines incontrol groups. |
| GO:0071598 neuronal ribonucleoprotein granule | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The one IBA in this family whose seed does not quite say what the annotation says. The single gene-level seed is mouse Arc, and its evidence is an MGI IDA on PMID:23936366 - a conditional knockout of TOG/Ckap5 in which Arc's role is that of the reporter TRANSCRIPT, chosen because it carries an A2RE element and is a known granule cargo. The Arc PROTEIN enters that paper only as a nascent translation readout imaged in the vicinity of granules, and as a steady-state immunostaining intensity; the paper never shows Arc protein to be a constituent of a dendritic transport granule. GO:0071598 is defined as a complex that 'transports translationally silenced mRNAs to dendritic synapses' - which describes Arc mRNA's situation well and Arc protein's less well. The RNA-containing assembly that Arc protein demonstrably builds is the virus-like capsid, a different structure with a different fate. Reason: Not removed: MGI curators read the full text, nascent Arc protein genuinely is imaged at granules, and an RNA-binding protein co-residing with its own transcript in an RNP is entirely plausible. But the seed evidence is about the transcript rather than the protein, so the annotation should not be read as a demonstrated protein localisation, and the node has only this one gene-level seed to rest on. Kept as non-core with the weakness recorded rather than laundered. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:88067 · Arc (Mus musculus), = UniProtKB:Q9WV31 SOURCE WEAK OR INFERRED Mouse Arc's IDA on PMID:23936366 is the only gene-level seed. That study is a TOG/Ckap5 conditional knockout using microinjected Cy5-labelled Venus-ARC reporter RNA to count granules; Arc protein is measured as nascent translation output at granules and as bulk immunostaining intensity. The evidence therefore establishes Arc mRNA as granule cargo more firmly than it establishes Arc protein as a granule component. PANTHER:PTN008562333 · PTHR15962 Arc IBD node, placed at Tetrapoda (taxon:32523) SUPPORTS TRANSFER Sole IBD node of PTHR15962, placed at Tetrapoda (taxon:32523). Its neuronal ribonucleoprotein granule assertion is seeded by a single gene-level donor, mouse Arc. Human ARC is a tetrapod Arc and sits inside the inheriting clade. The node deliberately excludes Drosophila Arc1 (Q7K1U0), which PANTHER places in the same family and subfamily but which is an independent Ty3/gypsy domestication; QuickGO confirms dArc1 carries no IBA from this node. The node placement itself is not in question - human ARC is inside the tetrapod clade - only the aboutness of the seed evidence. Supporting Evidence: PMID:23936366 ARC RNA was used as a reporter RNA for granule assembly and translation in control and TOG cKO neurons because it contains an A2RE sequence, is incorporated into granules and exhibits bursty translation in hippocampal neurons PMID:23936366 Translational output per granule was analyzed by single molecule imaging of newly synthesized Venus-ARC protein molecules in the vicinity of each granule as described previously PMID:29328916 These results suggest that Arc protein and its mRNA form a complex in neurons in vivo. |
| GO:0071598 neuronal ribonucleoprotein granule | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara projection of the same mouse annotation that seeds the IBA above, so it inherits the same limitation: the underlying study (PMID:23936366) assays Arc mRNA as granule cargo, not Arc protein as a granule component. Reason: Same judgement as the IBA row, reached automatically rather than phylogenetically. Two routes to one observation do not make the observation stronger. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SOURCE WEAK OR INFERRED Same donor annotation as the IBA row - mouse Arc IDA on PMID:23936366 - and the same transcript-versus-protein limitation. This row and the IBA are not independent support. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SOURCE WEAK OR INFERRED The Compara projection is mechanically correct - it is the Ensembl record for Q9WV31 - but it can only be as good as the mouse annotation it projects, which is the weak one. Supporting Evidence: PMID:23936366 In TOG cKO cultured neurons granule assembly and bursty translation of activity-regulated cytoskeletal associated (ARC) mRNA, an A2RE RNA, are disrupted. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Compara projection from mouse Arc, whose annotation is a set of SynGO IDA and IMP rows on Chowdhury et al. 2006. Arc's substrate is the AMPA-type glutamate receptor and its site of action is the excitatory postsynapse, so the synapse type is not incidental - it is the only synapse type at which the known mechanism can operate. Reason: SynGO-curated, mechanistically necessary, and more informative than the bare synapse term. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is SynGO IDA and IMP annotations on PMID:17088211. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. Supporting Evidence: PMID:17088211 Here, we demonstrate that Arc/Arg3.1 protein interacts with dynamin and specific isoforms of endophilin to enhance receptor endocytosis. PMID:24945773 Thus, degradation of Arc by clathrin-localized Triad3A regulates the availability of synaptic AMPA receptors and temporally tunes Arc-mediated plasticity at glutamatergic synapses. |
| GO:0099149 regulation of postsynaptic neurotransmitter receptor internalization | IEA GO_REF:0000107 | ACCEPT | Summary: Compara projection from mouse Arc, whose annotation is a set of SynGO IDA and IMP rows on Chowdhury et al. 2006. This is the most precisely characterised thing Arc does: it binds dynamin 2 and endophilin 2/3 through separate regions, both interactions are required for endosome association, and the perturbation works in both directions - overexpression enhances AMPAR endocytosis while Arc-null neurons show more surface AMPARs and slower endocytosis. Reason: Core molecular role, established with bidirectional perturbation, a defined interaction interface and matching immunogold EM localisation at the PSD margins where AMPARs are internalised. UniProt states the same in its FUNCTION block. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is SynGO IDA and IMP annotations on PMID:17088211, a study that perturbed Arc in both directions. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. Supporting Evidence: PMID:17088211 Here, we demonstrate that Arc/Arg3.1 protein interacts with dynamin and specific isoforms of endophilin to enhance receptor endocytosis. PMID:17088211 Conversely, Arc KO neurons display increased levels of surface AMPARs and decreased rates of endocytosis. file:human/ARC/ARC-uniprot.txt plasticity by promoting endocytosis of AMPA receptors (AMPARs) in |
| GO:0110077 vesicle-mediated intercellular transport | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from rat Arc's IDA on Pastuzyn et al. 2018. The GO definition - substances 'moved in extracellular vesicles between cells', enclosed in the lumen or in the vesicle membrane - is an exact description of what Arc was shown to do: EVs purified from wild-type but not Arc-null cortical neuron media transfer Arc mRNA into Arc-null recipient neurons, and the transferred mRNA is available for activity-dependent translation. Reason: Core. This is the process that the capsid, the RNA binding and the EV localisation all exist to produce, and it is the reason a retroelement Gag gene was worth domesticating. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29328916, using EVs purified from wild-type versus Arc-null neuron media as the controlled comparison. Supporting Evidence: PMID:29328916 Endogenous Arc protein is released from neurons in extracellular vesicles that mediate the transfer of Arc mRNA into new target cells, where it can undergo activity-dependent translation. PMID:29328916 These data indicate that endogenous Arc released via EVs is able to transfer Arc mRNA neuron-to-neuron. |
| GO:0170047 virus-like capsid | IBA GO_REF:0000033 | ACCEPT | Summary: The term GO created for this biology - its definition names Arc explicitly - propagated from a Tetrapoda-level node whose single gene-level seed is human ARC itself. The self-reference is the expected pattern, not circularity: human ARC's own IDA on PMID:33175445 is one of the descendant evidences the curator used, and the IBA then asserts something additional, that capsid formation is ancestral to tetrapods rather than a human peculiarity. That extra claim is independently true: Pastuzyn et al. found single-copy Arc orthologues throughout tetrapods and absent from all fish and other deuterostomes examined, which is precisely where taxon:32523 sits. Reason: Correct term, correct node, and the node's Tetrapoda placement is what keeps this annotation honest. Drosophila Arc1 sits in the same PANTHER family and subfamily and also forms capsids, but it is an independent Ty3/gypsy domestication; had the IBD been placed at the family root, a textbook case of convergent evolution would have been mislabelled as inheritance. Core - this is the defining structure of the protein. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008562333 · PTHR15962 Arc IBD node, placed at Tetrapoda (taxon:32523) SUPPORTS TRANSFER Sole IBD node of PTHR15962, placed at Tetrapoda (taxon:32523). Its virus-like capsid assertion is seeded by human ARC's own IDA on PMID:33175445. Human ARC is a tetrapod Arc and sits inside the inheriting clade. The node deliberately excludes Drosophila Arc1 (Q7K1U0), which PANTHER places in the same family and subfamily but which is an independent Ty3/gypsy domestication; QuickGO confirms dArc1 carries no IBA from this node. Verified in both directions: dArc1 carries three IDA rows for GO:0170047 and no IBA at all, and no FB identifier appears in any WITH/FROM of the human IBA rows, so the two lineages' capsid annotations are kept separate exactly as the phylogenomics in PMID:29328916 requires. UniProtKB:Q7LC44 · ARC (Homo sapiens), the target itself SUPPORTS TRANSFER The target's own IDA for this term (FlyBase, PMID:33175445). Appearing in the WITH/FROM of the IBA it receives is correct and expected; it signals that experimental grounding exists on the target itself and is not redundant with the phylogenetic claim. Supporting Evidence: PMID:29328916 Here, we show that Arc self-assembles into virus-like capsids that encapsulate RNA. PMID:29328916 Highly conserved, unique orthologs of the murine Arc genes were identified throughout the tetrapods (mammals, birds, reptiles, amphibians), but were conspicuously absent from all fish lineages and other deuterostomes examined (94 species). PMID:29328916 These results indicate that the tetrapod and fly Arc genes originated independently from distinct lineages of Ty3/gypsy retrotransposons but still share significant homology in the retroviral Gag domain. |
| GO:0170047 virus-like capsid | IDA PMID:33175445 Arc self-association and formation of virus-like capsids are... | ACCEPT | Summary: Direct evidence that purified Arc forms capsids, visualised by transmission and cryo-EM, with a point mutant of the 7-residue oligomerisation motif arrested at the dimer stage. Pastuzyn et al. independently measured the particles at 32 nm with a double-shell structure and showed they are endocytosed by recipient neurons. Reason: The single most characteristic property of this protein, and the reason GO:0170047 exists. Core. Supporting Evidence: PMID:33175445 Purified wild-type Arc formed capsids as shown by transmission and cryo-electron microscopy, whereas mutant Arc with disruption of the oligomerization motif formed homogenous dimers. PMID:29328916 Purified Arc capsids are endocytosed and are able to transfer Arc mRNA into the cytoplasm of neurons. |
| GO:1900271 regulation of long-term synaptic potentiation | IBA GO_REF:0000033 | ACCEPT | Summary: Two gene-level donors, mouse and rat Arc, each with an IMP from an independent perturbation design: antisense knockdown in rat hippocampus, and a CaMKII-phosphosite knock-in in mouse. Both converge on Arc controlling the late, consolidation phase of LTP rather than its induction. Reason: Well-seeded node, correct clade, correct term. Regulation-of is the right formulation: Arc is not part of the induction machinery but sets whether potentiation persists, and the Arc-null phenotype is an enhanced early phase with an absent late phase, which is modulation rather than execution. Core. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:88067 · Arc (Mus musculus), = UniProtKB:Q9WV31 SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IMP annotation on PMID:31151856, the CaMKII-phosphosite knock-in. PANTHER:PTN008562333 · PTHR15962 Arc IBD node, placed at Tetrapoda (taxon:32523) SUPPORTS TRANSFER Sole IBD node of PTHR15962, placed at Tetrapoda (taxon:32523). Its regulation of long-term synaptic potentiation assertion is seeded by two gene-level donors, mouse Arc and rat Arc, each carrying an independent IMP. Human ARC is a tetrapod Arc and sits inside the inheriting clade. The node deliberately excludes Drosophila Arc1 (Q7K1U0), which PANTHER places in the same family and subfamily but which is an independent Ty3/gypsy domestication; QuickGO confirms dArc1 carries no IBA from this node. RGD:62037 · Arc (Rattus norvegicus), = UniProtKB:Q63053 SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IMP annotation on PMID:10818134, the antisense knockdown that separated LTP maintenance from LTP induction. Supporting Evidence: PMID:10818134 Our studies show that disruption of Arc protein expression impairs the maintenance phase of LTP without affecting its induction and impairs consolidation of LTM for spatial water task training without affecting task acquisition or short-term memory. PMID:17088210 Moreover, they exhibit a biphasic alteration of hippocampal long-term potentiation in the dentate gyrus and area CA1 with an enhanced early and absent late phase. |
| GO:1900271 regulation of long-term synaptic potentiation | IEA GO_REF:0000107 | ACCEPT | Summary: Compara projection of the mouse IMP on Zhang et al. 2019, arriving at the same term as the IBA and the two ISS rows by a fourth route. Reason: Correct. Four concordant routes to one well-evidenced claim is redundancy rather than a problem; none of them is a weaker link that the others are propping up. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IMP annotation on PMID:31151856. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. Supporting Evidence: PMID:31151856 Arc is a synaptic protein essential for memory consolidation. PMID:17898216 These results indicate that Arc synthesis at 2 h is critical for LTP consolidation. |
| GO:1900271 regulation of long-term synaptic potentiation | ISS GO_REF:0000024 | ACCEPT | Summary: Explicit curator transfer from rat Arc, whose IMP is Guzowski et al. 2000. The experiment dissociates induction from maintenance, which is what makes the regulation-of term appropriate. Reason: Sound donor, sound transfer, core process. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IMP annotation on PMID:10818134. Supporting Evidence: PMID:10818134 Here, we investigated the role of the IEG Arc (also termed Arg3.1) in hippocampal plasticity. PMID:10818134 Thus, Arc appears to play a fundamental role in the stabilization of activity-dependent hippocampal plasticity. |
| GO:1900271 regulation of long-term synaptic potentiation | ISS GO_REF:0000024 | ACCEPT | Summary: Explicit curator transfer from mouse Arc, IMP on Zhang et al. 2019. Note the direction of that result: in the phosphosite knock-in, hippocampal LTP was normal and it was mGluR-LTD that changed, so the mouse donor's support for the LTP term comes from the broader Arc-null literature as much as from the knock-in itself. Reason: Sound donor and a well-established term. Flagged rather than downgraded: the mouse IMP is on a model in which LTP was explicitly reported as unchanged, so it is the rat donor and the Arc-null phenotype that carry this particular claim. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, a single-copy gene with no mammalian paralogue. Its GO:1900271 row is an IMP on PMID:31151856, a knock-in in which hippocampal LTP was in fact unchanged and mGluR-LTD was enhanced; the term is nonetheless correct for Arc on the wider knockout evidence (PMID:17088210, PMID:10818134). Supporting Evidence: PMID:31151856 We generated a mouse genetic model expressing mutant Arc that cannot be phosphorylated by CaMKII and found that baseline synaptic transmission and LTP in the hippocampus appear normal but metabotropic receptor-LTD is increased in magnitude. PMID:17088210 Moreover, they exhibit a biphasic alteration of hippocampal long-term potentiation in the dentate gyrus and area CA1 with an enhanced early and absent late phase. |
| GO:1900452 regulation of long-term synaptic depression | IEA GO_REF:0000107 | ACCEPT | Summary: Compara projection from mouse Arc, whose annotation is an IDA on Barylko et al. 2018 - the palmitoylation study, in which mutating the 94-CLCRC-98 cysteines abolished an Arc-dependent form of synaptic depression. Independent support comes from the CaMKII-phosphosite knock-in, where mGluR-LTD was enhanced, and from the Arc-null mouse, where LTD is impaired. Reason: Core. Arc is the effector that removes AMPA receptors during LTD, and the evidence includes both directions - loss of Arc impairs LTD, loss of the CaMKII brake on Arc oligomerisation enhances it. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29264923, plus corroborating IMP evidence on PMID:31151856. ensembl:ENSMUSP00000023268 · mouse Arc protein ENSMUSP00000023268, the Ensembl Compara record for Q9WV31 SUPPORTS TRANSFER Ensembl Compara pairs human ARC with this mouse protein model; it is the same entity as UniProtKB:Q9WV31 under an Ensembl identifier, so it adds a projection route rather than a second item of evidence. Supporting Evidence: PMID:29264923 Lastly, we demonstrate that mutation of these cysteines abolishes an Arc-dependent form of synaptic depression, pointing to a functional role for Arc palmitoylation in neurons. PMID:31151856 By contrast, mGluR-LTD evoked by bath application of (S)-3,5-dihydroxyphenylglycine (DHPG) revealed enhanced magnitude of depression in Arc 260/278 AA/AA slices (Figure 6D). |
| GO:1900452 regulation of long-term synaptic depression | ISS GO_REF:0000024 | ACCEPT | Summary: Explicit curator transfer of the same mouse evidence. The palmitoylation motif is intact in the human sequence, so the mechanistic basis transfers along with the orthology. Reason: Sound donor, sound transfer, core process. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29264923. Supporting Evidence: PMID:29264923 Thus, it appears that palmitoylation regulates at least a subset of Arc functions in synaptic plasticity. PMID:31151856 This finding suggests that the efficacy of mGluR-LTD is normally controlled by local CaMKII activity. |
| GO:1903561 extracellular vesicle | ISS GO_REF:0000024 | ACCEPT | Summary: Transfer from rat Arc, whose annotation is an IDA on Pastuzyn et al. 2018. Endogenous Arc is released from cortical neurons in extracellular vesicles, release is activity-dependent, and a C-terminal-domain deletion that prevents capsid assembly also prevents EV release - so the vesicular pool is not a contaminant but the output of the capsid pathway. UniProt lists 'Extracellular vesicle membrane' first among the human protein's locations. Reason: Core. This is the compartment in which the intercellular mRNA transfer happens, and without it the capsid has nowhere to go. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, 396 aa and a single-copy gene with no mammalian paralogue. Its own evidence for this term is an IDA annotation on PMID:29328916, which purified EVs from cortical neuron media and showed endogenous Arc in them. Supporting Evidence: PMID:29328916 Conversely, Arc-DeltaCTD-transfected HEK cells exhibited little expression in the EV fraction (Figure 3B), suggesting that proper Arc capsid assembly may be required for Arc release via EVs. PMID:29328916 These data indicate that endogenous Arc released via EVs is able to transfer Arc mRNA neuron-to-neuron. file:human/ARC/ARC-uniprot.txt SUBCELLULAR LOCATION: Extracellular vesicle membrane |
| GO:0005634 nucleus | ISS PMID:23749147 Arc in the nucleus regulates PML-dependent GluA1 transcripti... | NEW | Summary: GOA gives human ARC no nuclear location at all, yet nuclear Arc is a substantial and mechanistically defined pool. Korb et al. showed that nuclear Arc expression is regulated by synaptic activity in vivo and in vitro, mapped a nuclear localisation signal, a nuclear retention domain and a nuclear export signal in the protein, and showed that nuclear Arc raises PML body expression and lowers GluA1 transcription, downscaling synaptic strength. Chowdhury et al. independently noted nuclear enrichment of Arc when expressed alone in heterologous cells. Reason: A plain compartment gap. The nuclear pool is not incidental: it is how Arc mediates the transcriptional arm of homeostatic downscaling, a function distinct from its endocytic one, and it has dedicated targeting sequences. Coded ISS on mouse Arc because the experiments are murine; the NLS/NES architecture is sequence-encoded and so transfers with the orthology. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc. PMID:23749147 states 'We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro' and identifies the targeting sequences on the mouse protein; human and mouse Arc are both 396 aa with no mammalian paralogue, so the transfer is straightforward. Supporting Evidence: PMID:23749147 Arc expression is robustly induced by activity, and Arc protein localizes to both active synapses and the nucleus. PMID:23749147 We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain and a nuclear export signal. PMID:17088211 When expressed individually, Arc localized throughout the cytoplasm with enrichment in the nucleus and the plasma membrane. |
| GO:0030674 protein-macromolecule adaptor activity | ISS PMID:17088211 Arc/Arg3.1 interacts with the endocytic machinery to regulat... | NEW | Summary: The molecular-function half of this record is currently either uninformative or structural: four bare GO:0005515 protein binding rows from a yeast two-hybrid screen, mRNA binding, and structural molecule activity. None of them captures what Arc does at the synapse, which is to bring endophilin and dynamin together on a membrane so that they can act on AMPA receptors. Chowdhury et al. mapped the two interactions to distinct regions of Arc - UniProt records them as residues 89-100 for SH3GL1/SH3GL3 and 195-214 for DNM2 - and showed that both are required for Arc to associate with vesicles; Wu et al. state the recruitment directly. Reason: A missing molecular function, not a duplicate of an existing row. GO:0030674 is defined as an adaptor activity bringing two or more macromolecules into contact so they can function in a coordinated way, with 'protein recruiting activity' among its synonyms, which is precisely the described mechanism. It is the term the four uninformative protein binding rows would ideally have become, except that their partners (TBX18, S100P, CSRP2, SH2D4A) are not the adaptor partners, so this has to be added rather than substituted. Coded ISS on rat Arc, since the interaction mapping is rat and human biochemistry has not been done. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q63053 · Arc (Rattus norvegicus) SUPPORTS TRANSFER Rat Arc, the source of the interaction mapping in PMID:17088211 (yeast two-hybrid against dynamin 2 and endophilin 3, co-immunoprecipitation from rat forebrain P2 fractions, and deletion analysis showing both interactions are required for vesicle association). The interacting regions are annotated on the human UniProt record as residues 89-100 and 195-214 by similarity to this donor. Supporting Evidence: PMID:17088211 Here, we demonstrate that Arc plays a regulatory role in AMPAR trafficking via its interaction with components of the endocytic machinery, endophilin and dynamin. PMID:17088211 Distinct Regions of Arc are Required for Interactions with Endophilin and Dynamin, and Both Interactions are Required for Association with Vesicles PMID:22036569 Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both hebbian and non-hebbian forms of plasticity. file:human/ARC/ARC-uniprot.txt Interaction with SH3GL1 or SH3GL3 |
| GO:0060292 long-term synaptic depression | ISS PMID:17088210 Arc/Arg3.1 is essential for the consolidation of synaptic pl... | NEW | Summary: GOA carries the regulation-of parent (GO:1900452) but not the process itself. Arc is not merely a modulator of LTD - it is the effector that removes the receptors. Arc-null mice have significantly impaired LTD; rapid Arc translation is what sustains the increased AMPAR endocytosis rate underlying mGluR-LTD; and blocking Arc palmitoylation abolishes an Arc-dependent form of synaptic depression outright. Reason: Participation, not modulation. The endophilin/dynamin recruitment that Arc performs is a step in the LTD mechanism, in the same sense that the regulation-of term is a step in controlling it. Both terms are appropriate and the record currently has only one. Coded ISS on mouse Arc: the knockout phenotype is murine. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc. The germline Arc/Arg3.1 knockout (PMID:17088210) shows significantly impaired long-term depression, and two independent mouse manipulations - cysteine mutation of the palmitoylation motif (PMID:29264923) and CaMKII-phosphosite knock-in (PMID:31151856) - move LTD in opposite directions, which is what a required participant should do. Supporting Evidence: PMID:17088210 In addition, long-term depression is significantly impaired. PMID:29264923 Lastly, we demonstrate that mutation of these cysteines abolishes an Arc-dependent form of synaptic depression, pointing to a functional role for Arc palmitoylation in neurons. PMID:31151856 Arc is expressed at low basal levels in Purkinje cells and does not contribute to the early phase of LTD but is transcriptionally induced and is required for the protein synthesis-dependent late phase of LTD (Smith-Hicks et al., 2010). |
| GO:0098883 synapse pruning | ISS PMID:23791196 Arc/Arg3.1 is a postsynaptic mediator of activity-dependent ... | NEW | Summary: Developmental synapse elimination is absent from the human record entirely, although UniProt states it in the FUNCTION block. Mikuni et al. showed by Purkinje-cell-specific Arc knockdown that Arc mediates the final stage of climbing-fibre synapse elimination in the developing cerebellum, downstream of P/Q-type voltage-dependent calcium channels, and that knockdown leaves redundant climbing-fibre terminals on Purkinje cell somata. Reason: A distinct developmental process, mechanistically continuous with Arc's synaptic-weakening role but not covered by any plasticity term on the record. The perturbation is cell-type specific and epistatically placed, which is stronger than a correlative developmental observation. Coded ISS on mouse Arc since the work is murine; non-core relative to the capsid and AMPAR-endocytosis functions. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc. PMID:23791196 used Purkinje-cell-specific knockdown in mouse cerebellum and placed Arc downstream of P/Q-type VDCCs by occlusion. UniProt already carries the claim on the human entry as a by-similarity FUNCTION statement, so the transfer is consistent with the existing curation. Supporting Evidence: PMID:23791196 PC-specific Arc knockdown had no appreciable effect until around postnatal day 11 but significantly impaired CF synapse elimination thereafter, leaving redundant CF terminals on PC somata. PMID:23791196 We conclude that Arc mediates the final stage of CF synapse elimination downstream of P/Q-type VDCCs by removing CF synapses from PC somata. file:human/ARC/ARC-uniprot.txt Acts as a postsynaptic mediator of activity-dependent synapse |
| GO:0036336 dendritic cell migration | ISS PMID:28783680 Arc/Arg3.1 governs inflammatory dendritic cell migration fro... | NEW | Summary: Arc is not only neuronal. Ufer et al. found Arc/Arg3.1 strictly confined to skin-migratory dendritic cells, required for accelerated DC migration during inflammation, and acting through nonmuscle myosin II-dependent actin dynamics; the migration defect impaired T-cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. UniProt states this in the human FUNCTION block, but GO has no corresponding annotation. Reason: A genuine curation gap between UniProt and GO on the same protein. The immune role is peripheral to Arc's core capsid and synaptic functions but it is a real, separately evidenced process with a defined cytoskeletal mechanism, and it is the one context in which Arc's long-standing 'cytoskeleton-associated' name has a demonstrated functional payoff outside neurons. Coded ISS on mouse Arc; non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9WV31 · Arc (Mus musculus) SUPPORTS TRANSFER Mouse Arc. PMID:28783680 is a mouse study (Arc/Arg3.1-deficient mice, EAE and contact dermatitis models). UniProt already transfers the conclusion to the human entry as a by-similarity FUNCTION statement, so the ISS is consistent with existing curation. Supporting Evidence: PMID:28783680 We show that, in the skin, the neuronal plasticity molecule activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. PMID:28783680 Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. file:human/ARC/ARC-uniprot.txt cells and regulates fast dendritic cell migration, thereby regulating |
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Download this section (compressed HTML)Q: For the PAINT curators of PTHR15962: would it be worth recording the Tetrapoda placement of PTN008562333 as a deliberate exclusion rather than leaving it implicit in the node taxon? PANTHER assigns Drosophila Arc1 (Q7K1U0) to this family and to subfamily SF0 alongside vertebrate Arc, and dArc1 has independently accumulated IDA annotations for virus-like capsid, mRNA binding, mRNA transport, vesicle-mediated intercellular transport and regulation of neuronal synaptic plasticity - nearly the same term set the node propagates to tetrapods. Anyone reading the family without reading the node taxon would reasonably conclude the two sets are homologous inheritance, when the published phylogenomics says they are convergent domestications of different Ty3/gypsy lineages.
Suggested experts: GO_Central PAINT curators, PANTHER family curators
Q: For MGI: does the GO:0071598 IDA on mouse Arc (PMID:23936366) intend to assert that the Arc protein is a component of neuronal RNP granules, or that Arc mRNA is granule cargo? In that study Arc is the A2RE reporter transcript and the protein appears only as nascent translation output imaged near granules. The distinction matters beyond mouse, because this annotation is the sole gene-level seed of the IBD node that propagates the term to human, chicken and every other tetrapod Arc.
Suggested experts: MGI curators, GO_Central PAINT curators
Q: For UniProt: two ECO:0000269 anchors on the Q7LC44 subcellular-location block appear to over-read their citations. 'Cytoplasm, cytoskeleton {ECO:0000269|PubMed:21834987}' cites a paper whose ARC localisation figure shows diffuse cytoplasmic GFP-ARC with plasma-membrane enrichment, with the cytoskeletal connection coming from a knockdown phenotype rather than from localisation; the genuine localisation evidence is rat (PubMed:7857651). 'Cytoplasmic vesicle, clathrin-coated vesicle membrane {ECO:0000269|PubMed:24945773}' cites a paper reporting transient association with clathrin-coated pits. Both propagate into GO as IEAs through the SubCell mapping. Note also that PubMed:21834987 now carries an author correction (PubMed:39390519) about its siARC panels.
Suggested experts: UniProt curators
Q: For SynGO and GO_Central: is there a reason human ARC has no nuclear cellular component annotation? Nuclear Arc has a mapped NLS, nuclear retention domain and NES, is activity-regulated in vivo, and mediates a distinct PML-dependent transcriptional route to synaptic downscaling (PMID:23749147). The absence looks like an oversight rather than a judgement, since the same record carries far more peripheral locations such as acrosomal vesicle.
Suggested experts: SynGO curators, GO_Central curators
Experiment: Express and purify recombinant human ARC (Q7LC44) and image it by negative-stain and cryo-EM, scoring particle diameter and shell structure against the published rat values of ~32 nm and a double shell, with an oligomerisation-motif mutant as the negative control. In parallel, isolate extracellular vesicles from human iPSC-derived cortical neurons before and after depolarisation and quantify ARC protein and ARC mRNA in the vesicle fraction. Finally, incubate ARC-knockout human iPSC neurons with those vesicles, or with purified human ARC capsids, and measure acquired ARC mRNA by qRT-PCR with RNase-treated capsids and RNA-stripped capsids as controls. This converts the five ISS rows that currently carry the capsid pathway into direct human evidence.
Hypothesis: Human ARC forms RNA-containing capsids and transfers its own mRNA between human neurons, as rat Arc does.
Type: biochemical and cell-biological reconstitution
Experiment: Fractionate stimulated neuronal lysates on a density gradient and assay each fraction for Arc protein, ARC mRNA, and established granule markers (hnRNP A2, Staufen, FMRP), with and without RNase and with and without non-ionic detergent - transport granules and Gag-like capsids differ in all three properties. Complement this with super-resolution co-immunostaining of endogenous Arc protein and granule markers in dendrites, quantifying co-localisation against a same-cell randomised control. A negative result would justify retiring GO:0071598 from the Arc IBD node; a positive one would put it on evidence it does not currently have.
Hypothesis: The Arc protein is not a constituent of canonical dendritic transport RNP granules; its RNA-containing assembly is the capsid.
Type: subcellular fractionation and imaging
Experiment: Build a panel of Arc point mutants that dissects the oligomerisation surfaces already mapped on the N-lobe and C-lobe from the endophilin-binding region (residues 89-100) and the dynamin-binding region (residues 195-214), aiming for one mutant that binds partners but cannot assemble beyond a dimer and one that assembles but cannot bind. Assay each for capsid formation by EM, for surface AMPA receptor levels and endocytosis rate in Arc-null neurons, and for extracellular vesicle release. If endocytosis survives loss of high-order assembly, Arc has two functions; if it does not, the capsid is the active species at the synapse and the intercellular transfer is a consequence of the same machinery.
Hypothesis: Capsid assembly and AMPA receptor endocytosis are separable functions of the same interface.
Type: structure-guided separation-of-function mutagenesis
Experiment: Repeat the TIRF experiment that underlies the current annotation, but with dual-colour imaging of ARC alongside both clathrin light chain and dynamin, and score the timing of ARC arrival and departure relative to scission. A protein that arrives during pit maturation and leaves at uncoating is at the pit; one that persists on the vesicle after scission is on the vesicle membrane. This settles the GO:0030665 versus GO:0005905 question directly rather than by re-reading the published figures, and the same experiment would test whether the CCP-independent surface pool that Mabb et al. reported corresponds to a clathrin-independent endocytic route.
Hypothesis: Human ARC localises to clathrin-coated pits rather than to the membrane of budded clathrin-coated vesicles.
Type: live-cell TIRF microscopy
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Almost nothing about Arc's function has been measured on the human protein. Of the 57 GOA rows, three IDAs rest on one structural paper and two more on an overexpression experiment in a carcinoma cell line; everything mechanistic is rat or mouse, reaching the human record through ISS, IBA and Compara projection.
NARROWING BIOLOGY RESIDUAL_SUBGAP
What is known: Firmly established for the human protein: the sequence is 396 aa with the Gag N-lobe and C-lobe solved on human material (PDB 6TN7, 6TNQ, 6TQ0, 6YTU, 7R1Z, 7R23, 8QF4, 8QF5); purified recombinant human Arc reversibly self-associates into large soluble oligomers; and the 0.95 A structure of the human oligomerisation coil exists. Not established for the human protein: that human Arc capsids form, package RNA, are released in extracellular vesicles, transfer mRNA between human neurons, bind human endophilin or dynamin, or drive AMPA receptor endocytosis in human neurons. Every one of those is rodent-only.
Significance: Human and rodent Arc are the same length and highly conserved, so the transfers are reasonable and the annotations are honestly coded. But ARC is implicated in human neurodevelopmental and neurodegenerative disease, and there is a specific reason to check: the capsid pathway is a horizontal-transfer mechanism whose efficiency could differ between species without any change to the fold. Human iPSC-derived neurons make this testable now.
What would resolve it: Repeat the core Pastuzyn experiments with human sequence and human cells: purify recombinant human Arc and look for 32 nm double-shelled particles by cryo-EM; isolate extracellular vesicles from human iPSC-derived cortical neurons and assay Arc protein and ARC mRNA content; and test neuron-to-neuron transfer using ARC-knockout human neurons as recipients.
Gap: It is unresolved whether the Arc protein is a component of canonical dendritic transport RNP granules, or whether its only RNA-containing assembly is the virus-like capsid.
OPEN BIOLOGYCURATION CC_DARK
What is known: Established: ARC mRNA carries an A2RE element, is a bona fide granule cargo, and is translated in bursts at granules; and Arc protein binds RNA and builds capsids that encapsidate it. Not established: that Arc protein resides in the granules that carry its transcript. The single annotation asserting it (mouse Arc IDA on PMID:23936366, which seeds the human IBA) comes from a TOG/Ckap5 knockout study in which Arc protein is imaged only as nascent translation output near granules.
Significance: The two structures have opposite fates - a transport granule keeps mRNA inside the cell and releases it at a synapse, a capsid exports it to another cell - so which one Arc protein occupies determines whether GO:0071598 or GO:0170047 describes its RNA-associated pool. At present the record asserts both, on very unequal evidence.
What would resolve it: Co-immunostain endogenous Arc protein with established granule markers (hnRNP A2, Staufen, FMRP) in dendrites of stimulated neurons, and separate the two assemblies biochemically: granules and capsids differ in density and in detergent and RNase sensitivity, so a gradient fractionation with RNase and Triton controls would distinguish them directly.
Gap: GO can say that Arc forms a virus-like capsid but not that it assembles one, and not that it is a structural constituent of one.
OPEN ONTOLOGY RESIDUAL_SUBGAP
What is known: The cellular component exists and names Arc in its definition (GO:0170047). The matching process and function terms exist only in viral form (GO:0019069, GO:0039660) and are unusable for a host-encoded protein. Consequently Arc's assembly step is annotated as GO:0051260 protein homooligomerization and its capsid role as bare GO:0005198 structural molecule activity.
Significance: Domesticated retroelement Gag genes are a growing class - fly Arc1 and Arc2, PEG10, the PNMA family - and all of them will hit the same two missing terms. Without them the annotations cannot distinguish a capsid builder from any protein that trimerises.
What would resolve it: Add the two terms proposed in proposed_new_terms, as siblings of the viral terms under GO:0065003 and GO:0005198 respectively, mirroring the precedent already set by GO:0170047.
Gap: How the two halves of Arc's biology relate is unknown: whether capsid-mediated intercellular mRNA transfer is part of the same mechanism as AMPA receptor endocytosis, or a second function that happens to use the same interface.
OPEN BIOLOGY MF_DARK
What is known: Established: the same seven-residue N-terminal coil motif is required for capsid formation and for Arc-facilitated endocytosis, and CaMKII phosphorylation of the Gag N-lobe switches off both high-order oligomerisation and Arc's synaptic weakening action. Not established: whether an Arc capsid is the species that recruits endophilin and dynamin at the postsynaptic membrane, or whether endocytosis uses lower-order oligomers and the capsid is a separate, exported form. UniProt raises but does not settle a third possibility - that capsids are how eliminated synaptic material is removed.
Significance: This determines whether Arc has one molecular function with two outputs or two distinct functions, which is exactly the distinction core_functions is meant to make. It also determines whether the intercellular transfer is a signalling mechanism in its own right or a by-product of synaptic protein turnover.
What would resolve it: Separation-of-function mutants are the route. Point mutations that block higher-order assembly while preserving the endophilin- and dynamin-binding regions (and the converse) would test whether endocytosis needs the capsid state; combining them with single-particle imaging of tagged Arc at spines would show which oligomeric species is present when receptors are internalised.
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