ERLIN2 is an endoplasmic reticulum membrane protein whose canonical 339-amino-acid product contains a lumenal SPFH domain and assembles with ERLIN1 into large oligomeric complexes. These complexes provide a structural platform for selective protein handling and for associations with ER ubiquitin ligases. ERLIN2-dependent recruitment of RNF170 contributes to the ubiquitination and turnover of activated inositol 1,4,5-trisphosphate receptors, linking receptor abundance to calcium signaling. Erlin complexes also contribute to the clearance of selected misfolded ER proteins. ERLIN2 restrains SREBP activation through the ER sterol-regulatory machinery, while erlin loss alters cholesterol esterification and lipid storage. A role in sterol-dependent HMG-CoA reductase turnover varies with experimental context. ERLIN2-specific native cholesterol binding remains unresolved. Pathogenic ERLIN2 variants cause hereditary spastic paraplegia with recessive and dominant inheritance; their effects on assembly, partner selection and substrate handling can differ. The physiological functions of the reported 152- and 206-amino-acid products remain unestablished.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ERLIN2 inherits the experimentally supported ER-membrane location. Reason: Human O94905 leaf PTN002495868 lies below IBD node PTN000794169 in the saved PTHR15351 tree, and its ungapped MSA matches the 339-residue canonical sequence exactly. The source includes human ERLIN1, ERLIN2 and worm ERL-1; target self-evidence is legitimate. PMID:22269071 Figure 3 and Methods assay worm ERL-1-HA expressed in HeLa, not human ERLIN2. Target human ERLIN2-GFP and the conserved membrane-topology experiments independently support the location. No target-path NOT is present; the ERAD NOT branch is a different lineage. The supported natural ERLIN2 location is the ER membrane. Human ERLIN2-GFP in PMID:24217618 shows an ER distribution and cholesterol-dependent mobility (Figure 5; DNA constructs and FRAP Methods). Native human ERLIN2 is independently represented as O94905 residues 1–339 in Reactome entity 8866520, with its own ER-membrane compartment. The membrane association is consistent with the conserved erlin topology established in PMID:19240031, whose Rat-1/alphaT3-1 experiments and mouse constructs must not be relabeled as human assays. This refinement is gene-level and does not establish that every short natural product has the same localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000794169 SUPPORTS TRANSFER Actual IBD, target path and exact MSA verified; donor species and experimental scope preserved. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane GO_REF:0000033 |
| GO:0015485 cholesterol binding | IBA GO_REF:0000033 | UNDECIDED | Summary: ERLIN2-specific cholesterol binding remains unresolved despite positive sterol-probe and mixed-complex evidence. Reason: The old IBA source is absent from the current source snapshot. The current cholesterol-binding IBD at PTN002692334 is outside the ERLIN2 target path, although aggregate tree labels still mention the term; this establishes a provenance/version boundary, not biological loss. PMID:24217618 Figure 4B and Methods 56–57 measure purified human ERLIN1, whereas Figure 4C and Methods 58–60 measure native mouse ERLIN1/2 complexes. These do not identify an ERLIN2-specific cholesterol-binding site or affinity. The independently read PMID:23396283 supplementary Tables 1 and 3 identify human ERLIN2 in sterol-probe Group III, with strong UV-dependent labeling and PEA-DA selectivity but no threshold cholesterol competition (Table 1: 20, 3.1, 1.3; Table 3 competition 1.4). This supports sterol-analogue interaction but leaves the exact cholesterol-binding assertion unresolved. No absence of binding is asserted. The inherited quotation is preserved with its original reference. Whether the old source context is marked retired is separate integration bookkeeping and is not decided here. Supporting Evidence: PMID:24217618 Erlins bound cholesterol with specificity and strong cooperativity |
| GO:0032933 SREBP signaling pathway | IBA GO_REF:0000033 | MODIFY | Summary: Specify negative regulation of the SREBP pathway. Reason: The SREBP IBD at PTN001282580 is genuinely on the O94905 target path, with human ERLIN1 and ERLIN2 experimental descendants; neither self-WITH nor donor count is a defect. PMID:24217618 Figures 1–3 and the human-cell siRNA, SREBP-processing and immunoprecipitation Methods show that ERLIN2 restrains canonical SREBP activation under sterol sufficiency: single ERLIN2 depletion increases target transcripts and SREBP2 processing/nuclear accumulation, while erlin-associated regulatory partners decrease on sterol depletion. The mechanistic role is negative regulation, rather than the sterol-decrease signaling sequence itself. GO:2000639 is a current unrestricted BP term; this is an explicit lateral role correction, not a claim that it is an is_a descendant of GO:0032933. Endogenous human complexes are distinguished from the separate tagged experiment containing hamster SCAP; direct versus bridged interactions remain unresolved. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN001282580 SUPPORTS TRANSFER Inheritance is verified; target original supports the more precise regulatory role. Proposed replacements: negative regulation of SREBP signaling pathway Supporting Evidence: PMID:24217618 directly involved in regulating the SREBP machinery GO_REF:0000033 |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000002 | MODIFY | Summary: Refine the correctly mapped erlin-family ER location to ER membrane. Reason: Current InterPro IPR033294 (Erlin1/2) matches O94905 residues 1–314 and explicitly maps to ER and ubiquitin protein ligase binding. This is a family inference with target membership verified, not a claim that the whole SPFH superfamily has this location. The supported natural ERLIN2 location is the ER membrane. Human ERLIN2-GFP in PMID:24217618 shows an ER distribution and cholesterol-dependent mobility (Figure 5; DNA constructs and FRAP Methods). Native human ERLIN2 is independently represented as O94905 residues 1–339 in Reactome entity 8866520, with its own ER-membrane compartment. The membrane association is consistent with the conserved erlin topology established in PMID:19240031, whose Rat-1/alphaT3-1 experiments and mouse constructs must not be relabeled as human assays. This refinement is gene-level and does not establish that every short natural product has the same localization. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane GO_REF:0000002 |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic ER-membrane assertion matches target-specific evidence. Reason: ARBA00028685 condition set 35 matches the actual target FunFam 3.30.479.30:FF:000009 and Eukaryota. The accompanying UniProt subcellular-location mapping agrees with the natural ERLIN2 membrane record. The supported natural ERLIN2 location is the ER membrane. Human ERLIN2-GFP in PMID:24217618 shows an ER distribution and cholesterol-dependent mobility (Figure 5; DNA constructs and FRAP Methods). Native human ERLIN2 is independently represented as O94905 residues 1–339 in Reactome entity 8866520, with its own ER-membrane compartment. The membrane association is consistent with the conserved erlin topology established in PMID:19240031, whose Rat-1/alphaT3-1 experiments and mouse constructs must not be relabeled as human assays. This refinement is gene-level and does not establish that every short natural product has the same localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028685 SUPPORTS TRANSFER Exact target rule match and independent membrane evidence support the output. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane GO_REF:0000120 |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000002 | ACCEPT | Summary: ERLIN2 associates with specific ER ubiquitin ligases in its functional assemblies. Reason: The actual IPR033294 family mapping and O94905 match support the inference, and target-specific experiments provide independent evidence. PMID:21343306 Figures 1B and 2A–C show endogenous human ERLIN2 with gp78 in HEK293 cells and human SPFH2 constructs associated with gp78, Hrd1 and Trc8 in CHO-7 cells. Figure 5 identifies TMUB1-mediated bridging to gp78; these are cellular co-immunoprecipitation experiments, not a demonstration that every pair binds directly as purified proteins. PMID:24217618 Figure 3A independently recovers gp78 with endogenous human ERLIN2. The specific ligase-binding activity is supported without assigning ubiquitin-transfer catalysis to ERLIN2. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt Interacts with SYVN1 and RNF139 GO_REF:0000002 |
| GO:0032933 SREBP signaling pathway | IEA GO_REF:0000117 | MODIFY | Summary: Specify the experimentally demonstrated negative regulatory role. Reason: ARBA00087340 condition set 0 matches the target erlin FunFam and Chordata; the physical rule output is GO:0032933. PMID:24217618 Figures 1–3 and the human-cell siRNA, SREBP-processing and immunoprecipitation Methods show that ERLIN2 restrains canonical SREBP activation under sterol sufficiency: single ERLIN2 depletion increases target transcripts and SREBP2 processing/nuclear accumulation, while erlin-associated regulatory partners decrease on sterol depletion. The mechanistic role is negative regulation, rather than the sterol-decrease signaling sequence itself. GO:2000639 is a current unrestricted BP term; this is an explicit lateral role correction, not a claim that it is an is_a descendant of GO:0032933. Endogenous human complexes are distinguished from the separate tagged experiment containing hamster SCAP; direct versus bridged interactions remain unresolved. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00087340 SUPPORTS TRANSFER Target rule membership is sound; the original human assays refine the biological role. Proposed replacements: negative regulation of SREBP signaling pathway Supporting Evidence: PMID:24217618 directly involved in regulating the SREBP machinery GO_REF:0000117 |
| GO:0032991 protein-containing complex | IEA GO_REF:0000117 | MODIFY | Summary: Specify the ER protein-containing complex. Reason: ARBA00028902 condition set 381 matches the target FunFam but asserts only the broad protein-containing-complex root. Native and tagged ERLIN2 association with erlin assemblies is supported by PMID:19240031 and the human-cell experiments in PMID:24217618. The human Reactome ERLIN1:ERLIN2 complex contains the complete natural O94905 chain. GO:0140534 is a current protein-complex descendant located in the ER; no exact stoichiometry or equivalence of the short natural products is inferred. This refinement concerns the natural ER erlin assembly; the separate PMID:18468998 alpha1D-AR affinity-complex context remains a different, non-core assembly and is not relabeled as the ER complex. Proposed replacements: endoplasmic reticulum protein-containing complex Supporting Evidence: PMID:19240031 SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex GO_REF:0000117 |
| GO:0036503 ERAD quality control pathway | IEA GO_REF:0000117 | ACCEPT | Summary: The electronic ERAD rule agrees with the supported substrate-processing role. Reason: ARBA00029018 condition set 18 matches target FunFam and Catarrhini. PMID:19240031 Results Figures 1 and 5–7 show erlin association with activated IP3 receptors before substantial polyubiquitination, impaired receptor ubiquitination/degradation after depletion, and rescue/assembly dependence with preserved calcium mobilization. This supports a substrate-processing assembly contribution, not ERLIN2 protease or ligase catalysis. The operative perturbation/rescue experiments are Rat-1 cells and the tagged constructs are mouse; HeLa host cells do not change construct species. Human ERLIN2 evidence in PMID:21343306 independently connects its ligase-associated complex to sterol-regulated HMGCR ubiquitination/degradation, with acknowledged cell-context differences. The channel-regulated ERAD and HMGCR experiments do not establish universal necessity for all ERAD cargo. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00029018 SUPPORTS TRANSFER Exact relevant disjunct matches; independent experimental role supports the output. Supporting Evidence: PMID:19240031 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate GO_REF:0000117 |
| GO:0045541 negative regulation of cholesterol biosynthetic process | IEA GO_REF:0000117 | ACCEPT | Summary: ERLIN2 restrains cholesterol production through SREBP regulation and regulated HMGCR turnover. Reason: ARBA00085017 condition set 0 matches target FunFam and Chordata. In PMID:24217618 Figures 1B/1D and 2, single human ERLIN2 depletion increases HMGR/HMGS transcripts, cholesterol abundance and SREBP2 activation; fatostatin sensitivity and association with the regulatory apparatus support a negative regulatory role. PMID:21343306 Figure 3 independently shows ERLIN2-dependent sterol-regulated ubiquitination/degradation of endogenous HMGCR in HEK293 cells. These results concern regulation rather than sterol synthesis catalysis by ERLIN2. Lipid abundance is not a direct isotope-flux measurement, and HMGCR effects vary with cellular context. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00085017 SUPPORTS TRANSFER Target rule match and human ERLIN2 pathway evidence support negative regulation. Supporting Evidence: PMID:24217618 led to canonical activation of SREBPs and their target genes GO_REF:0000117 |
| GO:0045717 negative regulation of fatty acid biosynthetic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Retain the supported downstream regulation of the SREBP lipogenic program. Reason: ARBA00084177 condition set 1 matches target FunFam and Chordata. PMID:24217618 Figures 1B/1D show increased FASN/ACC1 transcripts and free-fatty-acid abundance after human ERLIN2 depletion, without increased triglyceride abundance. Figures 2–3 support the canonical SREBP mechanism and association with its regulatory machinery. These are positive regulatory data, not fatty-acid synthase activity by ERLIN2 or direct measurement of synthetic flux for every lipid class. This downstream lipogenic output is retained as a contextual consequence of the SREBP regulatory role rather than a separate defining core function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00084177 SUPPORTS TRANSFER Relevant target disjunct and positive human regulatory endpoints agree; downstream lipogenic output is contextual. Supporting Evidence: PMID:24217618 key transcription factors for cholesterol and fatty acid biosynthetic GO_REF:0000117 |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | KEEP AS NON CORE | Summary: Historical aggregate context records supported ERLIN2 association with the gp78 ERAD module. Reason: Actual PMID:21343306 Figures 1B, 2 and 5 support human ERLIN2/gp78 and related ER-ligase associations, with TMUB1-dependent bridging; the historical aggregate also included partners whose association does not establish a more specific ERLIN2 molecular activity. The current partner-resolved rows carry evidence-backed ligase-binding refinements where appropriate. Retain this retired aggregate as supported non-core interaction provenance under the campaign policy. Its inherited UniProt CC INTERACTION line reports an imported interaction and is not independent experimental corroboration; the actual original assays cited here provide the evidence. No purified binary affinity or all-product equivalence is inferred. |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | Summary: Historical ERAD-network context records supported ERLIN2 partner associations. Reason: The PMID:22119785 main workflow and source-specific records support human ERLIN2 association with ERLIN1 and ER ligases; the original supplementary peptide tables were not inspected. Independent PMID:21343306 Figure 2 establishes the ligase associations, and PMID:33961781 author-directed data independently recover ERLIN1–ERLIN2. Current partner-resolved rows preserve the specific assignments. Retain this retired aggregate as supported non-core interaction provenance under the campaign policy. The inherited UniProt CC INTERACTION quotation is a record of the same curated interaction source, not independent proof; no uninspected screening peptide row is claimed as verified. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt O94905; O75477: ERLIN1 |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | KEEP AS NON CORE | Summary: Cross-linking proteomics supports ERLIN2–ERLIN1 association. Reason: PMID:30021884 analyzes DSSO-cross-linked U2OS nuclear preparations, and the exact human pair is curated as EBI-20904152. The original main Methods and Results were read, but the original supplementary cross-linked peptide rows could not be recovered and no residue pair is asserted. The nuclear preparation is not proof of a soluble nucleoplasmic erlin complex: nuclear-envelope-associated ER can remain in such preparations. Retain the supported physical association and acknowledge the raw occurs_in nucleus context without rewriting it or assigning nuclear function. The inherited UniProt CC INTERACTION quotation is provenance for the curated interaction, not independent confirmation of the original cross-linked peptide pair. Independent human ERLIN1–ERLIN2 association is also present in the actually inspected PMID:33961781 author-directed affinity data; this supports the same partner relationship without pretending the unread cross-link peptide table was recovered. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt O94905; O75477: ERLIN1 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Historical proteome-scale context records supported ERLIN2 association with ERLIN1 and TMUB1. Reason: Actual PMID:33961781 author-directed edge data recover ERLIN1 bait–ERLIN2 prey in HCT116 and TMUB1 bait–ERLIN2 prey in 293T, using human FLAG-HA affinity proteomics and gene-level filtering. Independent PMID:21343306 Figure 5 supports the TMUB1 association. Retain this retired aggregate as supported non-core interaction provenance under the campaign policy, without product-resolved or purified binary claims. The inherited UniProt CC INTERACTION line is not independent corroboration of its originating interaction annotation. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt O94905; O75477: ERLIN1 |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | MODIFY | Summary: Refine the supported ER localization to ER membrane. Reason: GO_REF:0000052 describes HPA antibody imaging. The actual O94905 record uses HPA002025, whose antigen matches canonical residues 190–337, and reports supported ER localization in A-431 and U-251MG. The examined A-431 image supports the reported reticular compartment but does not by itself resolve bilayer topology. Raw U2OS staining is separately annotated plasma membrane/cytosol, so ER localization is not asserted to be exclusive. The supported natural ERLIN2 location is the ER membrane. Human ERLIN2-GFP in PMID:24217618 shows an ER distribution and cholesterol-dependent mobility (Figure 5; DNA constructs and FRAP Methods). Native human ERLIN2 is independently represented as O94905 residues 1–339 in Reactome entity 8866520, with its own ER-membrane compartment. The membrane association is consistent with the conserved erlin topology established in PMID:19240031, whose Rat-1/alphaT3-1 experiments and mouse constructs must not be relabeled as human assays. This refinement is gene-level and does not establish that every short natural product has the same localization. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane GO_REF:0000052 |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:19240031 An endoplasmic reticulum (ER) membrane complex composed of S... | ACCEPT | Summary: The ER membrane localization of ERLIN2 is supported. Reason: PMID:19240031 Figure 2 localizes endogenous SPFH2 to ER in Rat-1 cells and assesses membrane association in rodent cells; its tagged deletion studies use mouse constructs. Independently, PMID:16835267 directly examines human ERLIN2 membrane localization in transfected cells. Retain the established human localization while preserving the rodent scope of the cited 2009 experiments, without claiming all three natural products were assayed. Supporting Evidence: PMID:19240031 the ER membrane protein SPFH1 and its homolog SPFH2 form a heteromeric |
| GO:0036503 ERAD quality control pathway | IDA PMID:19240031 An endoplasmic reticulum (ER) membrane complex composed of S... | ACCEPT | Summary: The erlin complex participates in ER-associated substrate recognition and degradation. Reason: PMID:19240031 Figures 1, 4–7 show SPFH1/SPFH2 engagement of activated IP3 receptors before peak ubiquitination, dependence on complex assembly, knockdown effects and rescue. These are positive mechanistic contributions to substrate recognition and processing, not only a requirement inferred from cell viability. The operative native assays are rodent and the engineered proteins are mouse; PMID:21343306 independently establishes human ERLIN2 engagement of the HMGCR degradation machinery. Retain the ERAD role without assigning ubiquitin-transfer or protease activity to ERLIN2, requiring it for every ERAD substrate, or transferring the results to all shorter products. Supporting Evidence: PMID:19240031 mediates the ER-associated degradation of inositol 1,4,5-trisphosphate |
| GO:0045121 membrane raft | NAS PMID:34572057 Role of ERLINs in the Control of Cell Fate through Lipid Raf... | ACCEPT | Summary: ERLIN2 association with ER lipid-raft-like domains is supported. Reason: PMID:34572057 is a secondary review, whose Sections 2.4 and 3 describe ERLIN proteins in detergent-resistant membrane and MAM-associated raft-like domains. The localization has independent original support in PMID:16835267 Figures 4–7 and PMID:25204797 Table 1. Retain the membrane-raft annotation without treating the review as a new direct experiment or assuming every raft-associated function discussed belongs to ERLIN2. Supporting Evidence: PMID:16835267 define lipid-raft-like domains of the ER |
| GO:0045540 regulation of cholesterol biosynthetic process | IDA PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | MODIFY | Summary: ERLIN2 restrains cholesterol biosynthesis through SREBP regulation. Reason: PMID:24217618 Figures 1–3 establish the negative direction: human ERLIN2 depletion increases cholesterol-pathway transcripts, cellular cholesterol and SREBP activation, with pathway-specific inhibition and physical-association evidence. Replace unsigned regulation with GO:0045541 (negative regulation of cholesterol biosynthetic process), independently represented by the electronic cholesterol-regulation annotation. The study measures transcript abundance, processing and lipid pools rather than an isotope-resolved synthesis flux; no cholesterol-synthetic enzyme activity is assigned to ERLIN2. Proposed replacements: negative regulation of cholesterol biosynthetic process |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1839094 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 1839094 → 5691527 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-1839094 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1839098 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 1839098 → 1839061 → 5691527 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-1839098 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1839100 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 1839100 → 5691527 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-1839100 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655240 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 5655240 → 5655216 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-5655240 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655263 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 5655263 → 5655218 → 5655216 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-5655263 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655266 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 5655266 → 5655216 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-5655266 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655269 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 5655269 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-5655269 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655278 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 5655278 → 5655296 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-5655278 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655290 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 5655290 → 5655254 → 5655217 → 5655218 → 5655216 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-5655290 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5655326 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 5655326 → 5655316 → 5655328 → 5655216 → 5655215 → 8853273 → 8853166 → 8853122 reaches the ERLIN2–FGFR1 disease-fusion entity 8853122, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-5655326 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8853322 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 8853322 → 8853277 → 8853148 reaches the ERLIN2–FGFR1 disease-fusion entity 8853148, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8853322 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8853325 | REMOVE | Summary: Remove the disease-fusion localization projection from natural ERLIN2. Reason: The actual source route 8853325 → 8853271 → 8853164 → 8853148 reaches the ERLIN2–FGFR1 disease-fusion entity 8853148, not a natural ERLIN2 product. Its O94905 reference legitimately identifies the retained ERLIN2 segment, while modified-sequence records encode 185 ERLIN2 residues plus a 30-residue replacement and 822 FGFR1 residues (1,037 total). PMID:23558953 Figure 2 corroborates the fusion architecture; the paper is not claimed to image plasma-membrane localization and Supplementary Figure S6 remains unread. The Reactome fusion location can remain valid, but exporting it as a location of native UniProtKB:O94905 is a product-specificity error; remove this native-product annotation. Independent HPA HPA002025 U2OS staining is positive plasma-membrane/cytosol evidence, with an antigen at canonical residues 190–337 beyond the retained ERLIN2 fusion segment. That separate observation neither validates this fusion-derived source context nor establishes localization of every natural product. The inherited UniProt ER-membrane quotation is retained as historical natural-protein context, not as support for plasma membrane or evidence that ER and plasma-membrane localization are mutually exclusive. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8853325 |
| GO:0005515 protein binding | IPI PMID:30352685 Stasimon/Tmem41b localizes to mitochondria-associated ER mem... | KEEP AS NON CORE | Summary: Human ERLIN2 is recovered with TMEM41B/Stasimon. Reason: The actual PMC rendering of PMID:30352685 Results 3.1 and Figure 1D reports human GFP-STAS expressed in HEK293 cells, affinity purification and a follow-up ERLIN2 immunoblot; GFP and untransfected samples are controls and SMN is a negative interaction control. Thus the pair is supported despite the title emphasizing Stasimon and mouse development. The complete Methods and supplementary protein list remained unavailable, so no exact ERLIN2 product sequence or purified binary interaction is claimed. Stasimon developmental or phospholipid-scrambling functions are not transferred to ERLIN2. |
| GO:0032991 protein-containing complex | IDA PMID:18468998 Blood pressure is regulated by an alpha1D-adrenergic recepto... | KEEP AS NON CORE | Summary: ERLIN2 was recovered in an alpha1D-adrenergic receptor affinity complex. Reason: PMID:18468998 Table 3 reports ERLIN2 in TAP-alpha1D-AR material from HEK293 cells with 19 distinct peptides and 48% sequence coverage; the current source-specific interaction record EBI-21277437 is consistent with this result. This supports a contextual protein-containing assembly. The functional signalosome experiments focus on syntrophins and dystrophin-related components, not an ERLIN2-specific step. No more specific established GO complex is justified for this exact association, and it should not be relabeled as the ERAD complex or treated as a constitutive core signalosome subunit. The inherited PMID:19240031 erlin-complex quotation is retained solely as historical context and does not support alpha1D-AR signalosome membership. The positive support for this contextual assembly is PMID:18468998 Table 3 itself; the two complexes are not equated. Supporting Evidence: PMID:19240031 SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866542 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 8866542 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CFTR processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8866542 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 8866546 → 8866538 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CFTR processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8866546 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866551 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 8866551 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CFTR processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8866551 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866854 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 8866854 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CFTR processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8866854 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866856 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 8866856 → 8866848 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CFTR processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8866856 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8866857 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 8866857 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CFTR processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-8866857 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931264 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 9931264 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CD274 processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-9931264 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931298 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 9931298 → 9931282 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CD274 processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-9931298 |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-9931313 | ACCEPT | Summary: The reaction participant is native ERLIN2 in an ER-membrane complex. Reason: The actual Reactome participant chain is 9931313 → 8866531 → 8866522 → 8866520, terminating at entity 8866520, O94905 residues 1–339, Homo sapiens, with its own GO:0005789 compartment. ERLIN2 is a component of ERLIN1:ERLIN2 within the modeled ERAD assembly. The reaction concerns CD274 processing, but this location assertion does not assign VCP ATPase activity, RNF5/RNF185/HRD1 ligase chemistry, or direct binding of every substrate to ERLIN2. The route validates the ERLIN2 participant location independently of the event-level compartment. Human ERLIN2-GFP provides independent localization support. Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane Reactome:R-HSA-9931313 |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: Historical aggregate context records ERLIN2 association with RNF185 and RNF5. Reason: PMID:24019521 Methods and Results/Figure 4A recover endogenous ERLIN2 with FLAG-RNF185 and FLAG-RNF5 from human HEK293T cells, with control-vector comparison. These measured ligase associations fit the existing narrow ligase-binding core, as do the two current partner-resolved contexts. The experiments do not establish that ERLIN2 recruits these ligases to CFTR, catalyzes ubiquitination or is required for CFTR turnover. The inherited module quotation describes the ligase study; the actual Figure 4A supplies ERLIN2-specific association evidence. Supporting Evidence: PMID:24019521 RNF185 and RNF5 as a novel E3 ligase module |
| GO:0032933 SREBP signaling pathway | IMP PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | MODIFY | Summary: ERLIN2 negatively regulates SREBP pathway activation. Reason: PMID:24217618 Figures 1–3 show that human ERLIN2 depletion increases SREBP processing, nuclear accumulation and target transcription; fatostatin sensitivity, Insig turnover and ERLIN2 association with the SREBP–Scap–Insig machinery support an ER regulatory role. GO:0032933 describes the sterol-depletion-triggered ER-to-nucleus signal sequence; GO:2000639 more precisely captures the measured restraint of that sequence. This is not a claim that ERLIN2 cleaves SREBP or directly binds cholesterol with the recombinant ERLIN1 affinity reported in Figure 4. Proposed replacements: negative regulation of SREBP signaling pathway Supporting Evidence: PMID:24217618 led to canonical activation of SREBPs and their target genes |
| GO:0045541 negative regulation of cholesterol biosynthetic process | IMP PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | ACCEPT | Summary: ERLIN2 negatively regulates the cholesterol biosynthetic program. Reason: PMID:24217618 single-ERLIN2 knockdown in human cells increases HMGR/HMGS expression, cholesterol abundance and nuclear SREBP activity. Fatostatin sensitivity and association with the SREBP–Scap–Insig machinery provide a regulatory explanation beyond lipid accumulation alone. Retain the negative-regulation term with the limits of the transcript/processing/lipid-pool assays; the isolated human recombinant cholesterol-binding reagent in the paper is ERLIN1, not ERLIN2. Supporting Evidence: PMID:24217618 led to canonical activation of SREBPs and their target genes |
| GO:0045717 negative regulation of fatty acid biosynthetic process | IMP PMID:24217618 Erlins restrict SREBP activation in the ER and regulate cell... | KEEP AS NON CORE | Summary: ERLIN2 restrains the fatty-acid biosynthetic program in the tested human-cell context. Reason: PMID:24217618 Figure 1 reports increased FASN/ACC1 transcripts and free-fatty-acid abundance after erlin depletion, while Figure 2 connects the transcriptional response to the canonical SREBP pathway. ERLIN2 acts as a regulator of the pathway rather than as a fatty-acid synthetic enzyme. Retain this supported downstream regulatory consequence as non-core, bounded to the cell-based assays; unchanged triglyceride abundance and the lack of a direct synthesis-flux assay limit broader metabolic claims. Supporting Evidence: PMID:24217618 key transcription factors for cholesterol and fatty acid biosynthetic |
| GO:0045121 membrane raft | IDA PMID:25204797 Flotillin-1 facilitates toll-like receptor 3 signaling in hu... | ACCEPT | Summary: ERLIN2 is detected in detergent-resistant membrane material from human endothelial cells. Reason: PMID:25204797 actual Methods describe SILAC, sucrose-gradient detergent-resistant membrane isolation and human-database mass spectrometry. Table 1 explicitly identifies ERLIN2 O94905 (score 793; shFlot1/control ratio 0.58, SEM 0.10, three preparations). The operational raft association is consistent with the cholesterol-sensitive intracellular membrane fractions of human ERLIN2 in PMID:16835267. Preserve the raw HUVEC cell-type extension; these data do not assign ERLIN2 a TLR3-signaling role or distinguish plasma-membrane rafts from ER-associated raft material. Supporting Evidence: PMID:16835267 define lipid-raft-like domains of the ER |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000054 | MODIFY | Summary: Retain the ER localization and refine its independently established membrane context. Reason: GO_REF:0000054 is LIFEdb microscopy of expressed GFP-fusion cDNAs, not HPA antibody imaging. The current LIFEdb resource link redirects to a general proteomics page; the target-specific historic image and tagged construct could not be recovered. The positive compartment claim is independently resolved by human ERLIN2-GFP experiments rather than inferred from that access gap. The supported natural ERLIN2 location is the ER membrane. Human ERLIN2-GFP in PMID:24217618 shows an ER distribution and cholesterol-dependent mobility (Figure 5; DNA constructs and FRAP Methods). Native human ERLIN2 is independently represented as O94905 residues 1–339 in Reactome entity 8866520, with its own ER-membrane compartment. The membrane association is consistent with the conserved erlin topology established in PMID:19240031, whose Rat-1/alphaT3-1 experiments and mouse constructs must not be relabeled as human assays. This refinement is gene-level and does not establish that every short natural product has the same localization. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: file:human/ERLIN2/ERLIN2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane GO_REF:0000054 |
| GO:0005515 protein binding | IPI PMID:19240031 An endoplasmic reticulum (ER) membrane complex composed of S... | KEEP AS NON CORE | Summary: ERLIN2 associates with ERLIN1 in the erlin complex. Reason: PMID:19240031 Figures 3–4 show reciprocal recovery of native SPFH1/SPFH2 and association of tagged deletion constructs. The native complex experiments use rodent cells and the Methods identify mouse SPFH2 and SPFH1 constructs, even when expressed in HeLa. Independent human ERAD affinity data in PMID:22119785 support the same partner association. Retain supported binding without inferring binary affinity, a fixed subunit ratio, or equivalent activity of all three human products. Supporting Evidence: PMID:19240031 SPFH1 and its homolog SPFH2 form a heteromeric approximately 2 MDa complex |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:16835267 Erlin-1 and erlin-2 are novel members of the prohibitin fami... | ACCEPT | Summary: ERLIN2 is an ER membrane protein. Reason: PMID:16835267 Figures 4–7 combine membrane fractionation, intracellular detergent-resistant fractions and colocalization with ER markers. The Methods clone human ERLIN2 from U937 cDNA; tagged human protein is examined in mouse NIH3T3 cells and full-length GFP fusions in human HeLa cells. This distinguishes the protein species from the host cells and supports ER membrane localization. The engineered N-terminal targeting probes do not establish localization or function of the two shorter natural products. |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | KEEP AS NON CORE | Summary: Human ERLIN2–ERLIN1 association is supported. Reason: PMID:21343306 describes the SPFH complex and human SPFH2 affinity purification, but its original supplementary protein list was not inspected. Independent PMID:22119785 human ERAD affinity records explicitly contain ERLIN2–ERLIN1, and PMID:33961781 author data recover the pair in HCT116 cells. These establish the same interaction without claiming that the unread 2011 supplementary row was verified. The raw GOA record also carries an occurs_in nucleus extension; the generic binding decision does not validate a nucleoplasmic interaction or rewrite the imported source. |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | KEEP AS NON CORE | Summary: ERLIN2 associates with HMG-CoA reductase in a sterol-sensitive ER complex. Reason: PMID:21343306 Results and Figure 4 distinguish endogenous human reductase association in HEK293 cells from tagged hamster HMGCR (P00347) coexpressed with human SPFH2 and Insig-1 in CHO-7 cells. Insig-1 and gp78 enhance the association, so this is complex-mediated substrate engagement rather than a purified binary-binding assay. Retain the supported interaction and exact hamster partner identifier; do not assign HMGCR catalytic activity to ERLIN2. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | MODIFY | Summary: ERLIN2 associates with the E3 ubiquitin ligase SYVN1/HRD1. Reason: PMID:21343306 Figure 2B and Results compare human SPFH1/SPFH2 with tagged HRD1 in CHO-7 cells and recover HRD1 with SPFH2. Current UniProt Q86TM6 identifies human SYVN1 as an E3 ubiquitin ligase. The already represented GO:0031625 is therefore more informative than generic protein binding. Preserve the cellular co-immunoprecipitation scope; this does not demonstrate an isolated binary interface or ERLIN2 ubiquitin-transfer chemistry. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | KEEP AS NON CORE | Summary: ERLIN2 associates with TMUB1 in the gp78-associated ER complex. Reason: PMID:21343306 Figure 5B–E, Results and expression-plasmid Methods directly examine human tagged SPFH2 and TMUB1 in CHO-7 cells. TMUB1 hydrophobic-region deletions alter association and TMUB1 coexpression enhances SPFH2–gp78 recovery. TMUB1 is the bridge tested in those experiments; the pair alone does not establish an additional specific catalytic or adaptor activity for ERLIN2. Retain supported contextual binding without treating the engineered TMUB1 variants as natural ERLIN2 products. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | MODIFY | Summary: ERLIN2 associates with the E3 ubiquitin ligase AMFR/gp78. Reason: PMID:21343306 Figure 1B detects endogenous SPFH2 with gp78 in human HEK293 cells, and Figures 2A, 4D and 5E examine human tagged proteins, domain constructs and TMUB1-dependent enhancement in CHO-7 cells. Q9UKV5 is human AMFR, an E3 ubiquitin ligase. Refine generic binding to the already represented GO:0031625 while retaining the complex-mediated scope; the paper does not establish that the largely luminal ERLIN2 directly binds the cytosolic gp78 domain without an intermediary. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | Summary: The human ERAD interaction map supports ERLIN2–ERLIN1 association. Reason: PMID:22119785 uses S-tagged human baits expressed in HEK293 cells, detergent extraction, affinity purification and mass spectrometry. Current curated source records EBI-25769871 and EBI-25770016 explicitly contain the ERLIN2–ERLIN1 pair. The main workflow was read; original supplementary peptide tables and detailed Online Methods were not inspected. Retain supported binding without claiming pair-specific orthogonal validation, precise product boundaries, or validation of the raw occurs_in nucleus extension. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | MODIFY | Summary: The human ERAD interaction map supports ERLIN2 association with the E3 ligase SYVN1/HRD1. Reason: PMID:22119785 main workflow describes human HEK293 S-tag affinity proteomics; current source-specific records EBI-25770037 recover the assigned partner. Its E3 identity and the independent human-protein co-immunoprecipitation experiments in PMID:21343306 Figure 2 justify the already represented ubiquitin protein ligase binding term. The original screening supplementary peptide rows were not inspected, and the result does not imply an isolated binary interface, all-product equivalence, or that ERLIN2 is itself a ubiquitin ligase. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | MODIFY | Summary: The human ERAD interaction map supports ERLIN2 association with the E3 ligase AMFR/gp78. Reason: PMID:22119785 main workflow describes human HEK293 S-tag affinity proteomics; current source-specific records EBI-25771162 and EBI-25770556 recover the assigned partner. Its E3 identity and the independent human-protein co-immunoprecipitation experiments in PMID:21343306 Figure 2 justify the already represented ubiquitin protein ligase binding term. The original screening supplementary peptide rows were not inspected, and the result does not imply an isolated binary interface, all-product equivalence, or that ERLIN2 is itself a ubiquitin ligase. Proposed replacements: ubiquitin protein ligase binding |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex supports ERLIN2 association with ERLIN1 in HCT116 cells. Reason: PMID:33961781 author-directed edge data identify ERLIN1 bait and ERLIN2 prey in HCT116 (gene IDs 10613–11160, data line 13690). The actual Methods use human ORFeome C-terminal FLAG-HA baits and CompPASS-Plus filtering, then assemble observations at gene level. Retain supported association without claiming product-resolved equivalence or a binary interface. The raw occurs_in nucleus extension is retained as source context and is not independently established by whole-cell affinity purification. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex supports ERLIN2 association with TMUB1 in 293T cells. Reason: PMID:33961781 author-directed edge data identify TMUB1 bait and ERLIN2 prey in 293T (gene IDs 83590–11160, data line 33356). Human ORFeome C-terminal FLAG-HA affinity purification and gene-level CompPASS-Plus analysis support association, independently consistent with PMID:21343306 Figure 5. They do not identify an ERLIN2 product-specific binary interface or make ERLIN2 the experimentally tested TMUB1 bridge. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: ERLIN2 associates with the E3 ubiquitin ligase RNF185 in human cells. Reason: PMID:24019521 actual Results and Figure 4A show endogenous ERLIN2 recovered by FLAG-RNF185 immunoprecipitation from HEK293T cells, with control-vector comparison; Methods specify the antibodies, transfection and detergent conditions. This is positive evidence for the specific ligase-association activity already represented by the narrow ERLIN2 ligase-binding core. Acceptance is based on the measured cellular association, not merely a same-term consistency rule or the ligases’ CFTR phenotype. The CFTR turnover and ubiquitination experiments perturb the ligases rather than ERLIN2, so they do not establish ERLIN2 catalysis or a universal requirement for this particular pair in ERAD. The normal cache is truncated despite its access flag; this assessment uses the recovered original text. The assay permits complex-mediated association and does not establish a purified binary interface or universal recruitment mechanism. Supporting Evidence: |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:24019521 RNF185 is a novel E3 ligase of endoplasmic reticulum-associa... | ACCEPT | Summary: ERLIN2 associates with the E3 ubiquitin ligase RNF5 in human cells. Reason: PMID:24019521 actual Results and Figure 4A show endogenous ERLIN2 recovered by FLAG-RNF5 immunoprecipitation from HEK293T cells, with control-vector comparison; Methods specify the antibodies, transfection and detergent conditions. This is positive evidence for the specific ligase-association activity already represented by the narrow ERLIN2 ligase-binding core. Acceptance is based on the measured cellular association, not merely a same-term consistency rule or the ligases’ CFTR phenotype. The CFTR turnover and ubiquitination experiments perturb the ligases rather than ERLIN2, so they do not establish ERLIN2 catalysis or a universal requirement for this particular pair in ERAD. The normal cache is truncated despite its access flag; this assessment uses the recovered original text. The assay permits complex-mediated association and does not establish a purified binary interface or universal recruitment mechanism. Supporting Evidence: |
| GO:0036503 ERAD quality control pathway | IBA GO_REF:0000033 | ACCEPT | Summary: The verified inherited ERAD assembly role is supported. Reason: IBD node PTN000794169 lies on the exact ERLIN2 target path. The current NOT/IRD node PTN002692340 is outside that path; the worm paper's negative physiological findings are not transferred to human ERLIN2. PMID:19240031 Results Figures 1 and 5–7 show erlin association with activated IP3 receptors before substantial polyubiquitination, impaired receptor ubiquitination/degradation after depletion, and rescue/assembly dependence with preserved calcium mobilization. This supports a substrate-processing assembly contribution, not ERLIN2 protease or ligase catalysis. The operative perturbation/rescue experiments are Rat-1 cells and the tagged constructs are mouse; HeLa host cells do not change construct species. Human ERLIN2 evidence in PMID:21343306 independently connects its ligase-associated complex to sterol-regulated HMGCR ubiquitination/degradation, with acknowledged cell-context differences. The channel-regulated ERAD and HMGCR experiments do not establish universal necessity for all ERAD cargo. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000794169 SUPPORTS TRANSFER Actual node/MSA/NOT path checked; mammalian substrate-processing experiments support the target role. |
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Download this section (compressed HTML)Q: Does human ERLIN2 itself bind native cholesterol, or does binding require ERLIN1 or a defined erlin complex, and how does that distinction affect SREBP restraint and cholesterol esterification?
Q: Which ERLIN2 assembly surfaces control partner selection and substrate handling, and can TMUB1 and RNF170 occupy the same erlin assembly simultaneously?
Q: How do verified ERLIN2 disease variants alter cargo handling or partner recruitment despite apparently preserved gross oligomerization, and is RNF213 causally involved in the reported Val71Ala cellular phenotype?
Q: Are the reported 152- and 206-amino-acid ERLIN2 products expressed as stable proteins, and do they localize or assemble with the canonical product?
Experiment: Compare composition-defined human ERLIN2, ERLIN1 and mixed complexes in native cholesterol-binding and photoaffinity assays, with competition, no-probe controls and matched stability/oligomerization measurements. Establish which protein binds before assigning a site or interpreting SREBP phenotypes as binding defects.
Experiment: Reconstitute erlin assemblies with TMUB1, RNF170 and an activated IP3R substrate to separate partner occupancy, substrate recognition and ubiquitin transfer; use the same assembly perturbations in misfolded A1AT-NHK/TTR-D18G turnover assays to test whether receptor handling and quality control use common interfaces.
Experiment: Use isogenic correction or introduction of sequence-verified disease variants at endogenous expression levels, coupled to cargo turnover and partner-association measurements. For the Val71Ala/RNF213 model, test RNF213 depletion and rescue, IP3R1 ubiquitination and half-life before assigning a degradation mechanism.
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