JIP4 (systematic name YDR475C; "Jumonji-interacting protein 4") is a large (876-residue) intrinsically disordered protein of Saccharomyces cerevisiae whose molecular function has not been experimentally determined. Its sequence is dominated by disorder and low-complexity, compositionally biased tracts, including basic/acidic repeats, and it is placed in the serine/arginine repetitive matrix protein family (PANTHER PTHR23148), whose metazoan members (SRRM1/SRm160) are nuclear SR-related splicing coactivators; JIP4 itself lacks the folded PWI nucleic-acid-binding domain that defines those splicing proteins, and no splicing or RNA-related activity has been demonstrated for it in yeast. The current UniProt snapshot cross-references two newly defined yeast JIP4 Pfam domains, JIP4_N and JIP4_helical, whose activity is not yet known. JIP4 is a phosphoprotein, with multiple serine residues phosphorylated in vivo (including cyclin-dependent-kinase-1-dependent sites) as detected by large-scale phosphoproteomics. The gene is non-essential; deletion is viable, and it has a paralog, YOR019W, arising from the whole-genome duplication that is likewise uncharacterized.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005681 spliceosomal complex | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Homology-only (IBA) inference propagated from the metazoan SRRM1/SRm160 orthologs in PANTHER family PTHR23148. There is no experimental evidence that yeast JIP4 is a spliceosome component, and this transfer is biologically questionable. Reason: This annotation is propagated from the all-eukaryote PTN000567596 node in the serine/arginine repetitive matrix family (with/from human SRRM1 Q8IYB3 and mouse Srrm1 MGI:1858303). The family placement reaches JIP4, but JIP4 lacks the PWI nucleic-acid-binding domain that defines the SRm160/SRRM1 splicing coactivators (UniProt cross-references the yeast JIP4_N/JIP4_helical PF29926/PF29925 families but still has no PWI, RRM, or positioned FT DOMAIN features). The S. cerevisiae spliceosome has been exhaustively purified and characterized, and JIP4 has never been reported as a spliceosome subunit; the known yeast counterparts of the human SR-related nuclear-matrix splicing proteins are other proteins (e.g. Cwc21/YDR482C). The annotation is therefore retained but flagged as a likely over-annotation of an uncharacterized gene rather than as core function. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q8IYB3 · SRRM1 (human) SUPPORTS SOURCE BUT NOT TARGET Human SRRM1/SRm160 is a bona fide PWI-domain spliceosome/EJC coactivator; the spliceosome-membership term is sound for the source but should not transfer to the PWI-less, uncharacterized yeast protein. MGI:MGI:1858303 · Srrm1 (mouse) SUPPORTS SOURCE BUT NOT TARGET PANTHER:PTN000567596 · PTHR23148:SF0 ancestral node SUPPORTS SOURCE BUT NOT TARGET PTN000567596 places spliceosomal-complex membership at the root of PTHR23148; that source assertion is valid for PWI-containing SRRM1/SRm160 descendants such as human and mouse SRRM1 but over-broad for PWI-less, uncharacterized yeast Jip4. Supporting Evidence: file:yeast/JIP4/JIP4-uniprot.txt PANTHER; PTHR23148; SERINE/ARGININE REGULATED NUCLEAR MATRIX PROTEIN; 1. |
| GO:0048024 regulation of mRNA splicing, via spliceosome | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Homology-only (IBA) inference of a splicing-regulation role from metazoan/ Drosophila SRRM1-family members. Not supported by any experimental evidence in yeast and biologically doubtful given the absence of the defining PWI domain. Reason: As for the spliceosomal-complex annotation, this biological-process term is transferred from SRRM1/SRm160 orthologs (with/from FB:FBgn0036340 and PANTHER PTN000567596) purely on family membership. JIP4 has no demonstrated RNA-binding or splicing activity, lacks the PWI domain, and does not appear in yeast spliceosome or splicing-regulator datasets. The specific SRm160-style splicing-coactivation role has not been shown for yeast Jip4, so this target branch is best treated as functionally divergent from the animal SRRM1-family sources. Retained but flagged as a likely over-annotation rather than established or core function. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: FB:FBgn0036340 · Drosophila SRRM1-family member SUPPORTS SOURCE BUT NOT TARGET PANTHER:PTN000567596 · PTHR23148:SF0 ancestral node SUPPORTS SOURCE BUT NOT TARGET PTN000567596 places spliceosomal mRNA-splicing regulation at the root of PTHR23148 based on animal SRRM1-family splicing regulators; that source biology has not been shown to transfer to intron-poor budding yeast Jip4, which lacks a PWI domain and has no demonstrated RNA-processing role. Supporting Evidence: file:yeast/JIP4/JIP4-uniprot.txt PANTHER; PTHR23148; SERINE/ARGININE REGULATED NUCLEAR MATRIX PROTEIN; 1. |
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: Root molecular_function term with the ND (No biological Data available) evidence code, correctly recording that no molecular function has been determined for JIP4. Reason: The ND annotation to the MF root is an honest placeholder for an uncharacterized gene. No experimentally supported molecular activity exists for JIP4, and no folded catalytic or binding domain is identifiable in its sequence, so retaining the ND root annotation accurately conveys the molecular-function-dark status. It does not represent a core function. The literature-search record in JIP4-deep-research-falcon.md finds no study of this S. cerevisiae gene product that identifies a molecular function. Supporting Evidence: file:yeast/JIP4/JIP4-deep-research-falcon.md No enzymatic activity, substrate specificity, or defined biochemical role has been experimentally determined. |
| GO:0005575 cellular_component | ND GO_REF:0000015 | ACCEPT | Summary: Root cellular_component term with ND evidence, recording that JIP4's subcellular localization has not been experimentally established. Reason: No experimental localization data are available for JIP4 (UniProt records no subcellular-location annotation). While the disordered, compositionally biased sequence is suggestive of a possible nuclear/RNA-associated localization, this is not established, so the ND root annotation is an appropriate honest placeholder. The literature-search record in JIP4-deep-research-falcon.md finds no study of this S. cerevisiae gene product that identifies a cellular location. Supporting Evidence: file:yeast/JIP4/JIP4-deep-research-falcon.md No published subcellular localization data specific to JIP4 were identified in the literature surveyed. |
| GO:0008150 biological_process | ND GO_REF:0000015 | ACCEPT | Summary: Root biological_process term with ND evidence, recording that no biological process/pathway has been assigned to JIP4. Reason: JIP4 is non-essential (deletion viable) with no defined loss-of-function phenotype beyond viability and no assigned pathway. The ND root annotation correctly captures the biological-process-dark status of this gene. The literature-search record in JIP4-notes.md finds no study of this S. cerevisiae gene product that identifies a biological process. Supporting Evidence: file:yeast/JIP4/JIP4-notes.md - Biological process / pathway — unknown (ND at the BP root). |
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Download this section (compressed HTML)Q: Does JIP4 physically associate with the JmjC transcription factor Gis1 (as its name implies) or with another Jumonji-family protein, and does it function in the Rim15/TOR/Sch9 nutrient-signaling / calorie-restriction pathway?
Q: Does JIP4 bind RNA and/or associate with the spliceosome or other mRNP complexes in yeast, or has the ancestral SRRM1-type splicing function been lost in this PWI-less, RS-rich protein?
Q: Where does JIP4 localize in the cell, and do its low-complexity biased regions drive nuclear or condensate localization?
Q: What is the functional relationship between JIP4 and its whole-genome-duplication paralog YOR019W, and does the double deletion reveal a phenotype masked by redundancy?
Q: What is the functional consequence of the Cdk1-dependent phosphorylation of JIP4, and is JIP4 a cell-cycle-regulated protein?
Experiment: Affinity-purify epitope-tagged JIP4 from yeast and identify co-purifying proteins and RNAs by mass spectrometry and RNA sequencing; test for direct RNA binding in vitro; assay splicing of intron-containing reporters in jip4 (and jip4 yor019w) mutants.
Hypothesis: JIP4 retains an ancestral RNA-processing/spliceosome-associated role inferred from its SRRM1-family membership.
Experiment: Construct jip4, yor019w, and jip4 yor019w deletion strains and phenotype them across stress, cell-cycle, and iron-availability conditions; determine JIP4 subcellular localization by endogenous fluorescent tagging.
Hypothesis: JIP4 has a non-redundant cellular role revealed only in combination with its paralog YOR019W or under specific stress conditions.
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular function of JIP4 is entirely unknown. No biochemical activity has been demonstrated, and its highly disordered sequence contains no recognizable catalytic or PWI/RRM nucleic-acid-binding domain. The animal-seeded spliceosome/splicing IBAs are unverified, and the plant-seeded root RNA-binding IBD is a family-level assertion rather than target-specific evidence for yeast JIP4.
OPEN BIOLOGY WHOLLY_DARK
What is known: It is firmly established that JIP4 is expressed as a protein (evidence at protein level) and is phosphorylated in vivo at multiple serines. It is assigned to the serine/arginine repetitive matrix family (PTHR23148) whose metazoan members are SR-related splicing coactivators. What is missing is any direct biochemical or genetic evidence of an activity for the yeast protein.
Significance: JIP4 is a conserved-family member left functionally dark in one of the best-studied eukaryotes; assigning its activity would test whether the metazoan SRRM1 splicing function is ancestral or a lineage-specific innovation, and would remove a genuine hole in the yeast proteome annotation.
What would resolve it: Direct biochemical assays (RNA/DNA-binding, association with spliceosomal or mRNP complexes by affinity purification-mass spectrometry), determination of subcellular localization, and phenotyping of jip4 deletion (including the jip4 yor019w double mutant) under diverse conditions would define or exclude an activity.
Provenance (the field's own admissions):
Gap: It is unknown whether the metazoan SRRM1/SRm160 splicing function transfers to yeast JIP4 at all: whether JIP4 binds RNA, associates with the spliceosome, or regulates mRNA splicing has never been tested experimentally, and the current spliceosome/ splicing GO annotations are homology-only (IBA) inferences.
OPEN BIOLOGY MF_DARK
What is known: The S. cerevisiae spliceosome and its regulators are extensively characterized, and JIP4 has not been identified as a component in those studies; the established yeast counterparts of human SR-related nuclear-matrix splicing proteins are other genes. JIP4 lacks the PWI domain that mediates the SRm160/SRRM1 splicing coactivator function.
Significance: Resolving this would either validate or correct the IBA-propagated splicing annotations, clarifying whether a divergent, PWI-less SR-repetitive-matrix protein retains any role in yeast RNA processing.
What would resolve it: Test for RNA binding and for physical/functional association with the spliceosome (co-purification, CLIP-type RNA interaction mapping, splicing-reporter assays in jip4 mutants), and compare against known yeast SR-related splicing factors.
Provenance (the field's own admissions):
Gap: The subcellular localization of JIP4 has not been experimentally determined, and its biological process/pathway and loss-of-function phenotype (beyond viability of the deletion) are unknown, including its functional relationship to the whole-genome-duplication paralog YOR019W.
OPEN BIOLOGY BP_DARK
What is known: JIP4 is non-essential; the jip4 deletion is viable and the yor019w deletion is viable. JIP4 appears in high-throughput interactome and phosphoproteome datasets but with no curated functional interpretation, and no dedicated study of the yeast protein has been reported.
Significance: A defined localization, phenotype, and paralog relationship would place JIP4 in a cellular process and indicate whether functional redundancy with YOR019W is masking its role.
What would resolve it: Endogenous fluorescent tagging for localization, condition-dependent phenotyping of jip4 single and jip4 yor019w double deletions, and interpretation of its physical interactors, together with functional analysis of its Cdk1-dependent phosphosites.
Provenance (the field's own admissions):
Gap: The molecular basis of the "Jumonji-interacting protein" name is not established: it is unclear whether JIP4 physically or functionally associates with the JmjC-domain transcription factor Gis1 (or another Jumonji-family protein), and if so what that interaction does, so any link to the Rim15/TOR/Sch9 nutrient-signaling and calorie-restriction pathway is hypothetical.
OPEN BIOLOGY MF_DARK
What is known: The name implies identification of JIP4 as a Gis1-associated factor, and Gis1 is a well-characterized JmjC zinc-finger transcription factor downstream of Rim15/TOR/Sch9. What is missing is any confirmed, mechanistically characterized JIP4-Gis1 (or JIP4-Jumonji) interaction and its functional consequence.
Significance: Confirming or refuting a JIP4-Gis1 association would either connect this dark gene to a defined nutrient-signaling/chromatin transcription pathway or remove a misleading name-based assumption.
What would resolve it: Co-immunoprecipitation/affinity purification to test a direct JIP4-Gis1 interaction, and epistasis/phenotyping of jip4 in Rim15/TOR/Sch9-pathway and calorie-restriction assays.
Provenance (the field's own admissions):
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Download this section (compressed HTML)Protein of unknown function; previously annotated as two separate ORFs, YDR474C and YDR475C, which were merged as a result of corrections to the systematic reference sequence; JIP4 has a paralog, YOR019W, that arose from the whole genome duplication
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