COS9 (systematic name YKL219W) is a Saccharomyces cerevisiae membrane protein of the subtelomeric DUP240/COS (COnserved Sequence) multigene family (COS1-COS10, COS12), which is largely uncharacterized at the molecular level. It is a multi-pass integral membrane protein of 407 residues containing tandem DUP domains (Pfam PF00674; InterPro IPR001142) and a very high lysine content (~8% of residues). Cos family members localize to endosomes and act in the multivesicular body (MVB) sorting pathway, where they cluster into ubiquitin-rich endosomal microdomains that concentrate and trap cargo β including ubiquitinated membrane proteins and GPI-anchored proteins β to promote their incorporation into intralumenal vesicles and delivery to the vacuole for degradation. The Cos proteins are themselves heavily ubiquitinated by the Rsp5 ubiquitin ligase system and are proposed to supply a ubiquitin sorting signal in trans to non-ubiquitinated cargo. Expression of COS genes is induced under nutrient (niacin/NAD+) stress through relief of Sir2-dependent subtelomeric silencing. No molecular (catalytic or binding) activity is known for the Cos family, which remains enzymatically uncharacterized.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: COS9 is a multi-pass integral membrane protein of the DUP/COS family, with three UniProt-predicted transmembrane helices (and a family model of four membrane-spanning segments). Membrane localization is well supported by domain architecture and is the most defensible COS9-specific cellular component. Accepted; the more specific endosomal membrane location is captured by the endosome annotation. Supporting Evidence: PMID:25942624 Cos proteins are comprised of ~380 residues, predicted to form 4 membrane spanning segments that bridge 2 small extracellular loops and larger cytosolic N and C-terminal tails |
| GO:0005768 endosome | ISS PMID:25942624 A family of tetraspans organizes cargo for sorting into mult... | KEEP AS NON CORE | Summary: Endosome localization is annotated by ISS with WITH/FROM SGD:S000003922, which is the paralog COS5 (YJR161C) β the experimentally characterized Cos representative. In that study Cos proteins localize to peri-vacuolar/late endosomal (class E) compartments and form endosomal microdomains. This is a biologically plausible homology-based compartment assignment for Cos9; it has not been measured on Cos9 itself, so it is kept as a well-supported non-core (homology) annotation rather than removed on paralog grounds. Supporting Evidence: PMID:25942624 A strong FRET signal between Cos5-GFP and Cos5-mCherry was only found at peri-vacuolar / late endosomal structures of wild-type cells |
| GO:0043328 protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway | ISS PMID:25942624 A family of tetraspans organizes cargo for sorting into mult... | KEEP AS NON CORE | Summary: This biological-process annotation captures the Cos family role β promoting MVB sorting of cargo for ubiquitin-dependent vacuolar degradation β and is transferred to Cos9 by ISS (WITH/FROM SGD:S000003922 = COS5). The experimental basis (whole-family cosΞ deletion plus Cos5 assays) establishes this role for the family; Cos9's individual contribution has not been directly tested, but the annotation is the best available statement of Cos9's probable function and is retained. Kept as non-core because it is homology-based and describes a process rather than a Cos9-specific molecular activity. Supporting Evidence: PMID:25942624 These data suggest Cos proteins mediate efficient sorting of a wide number of MVB cargoes. |
| GO:0003674 molecular_function | ND GO_REF:0000015 | ACCEPT | Summary: No molecular function has been assigned to COS9, and the DUP/COS family is enzymatically uncharacterized (InterPro IPR001142 describes it as membrane proteins "of unknown function"). The ND (no data) annotation accurately records this molecular- function gap. Accepted as an honest statement of the unknown; see knowledge_gaps. |
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Download this section (compressed HTML)Q: Does Cos9, like Cos5, localize to endosomal microdomains and become ubiquitinated, and is it required (individually or redundantly) for MVB sorting of ubiquitinated and GPI-anchored cargo? All current COS9 functional annotations are ISS transfers from Cos5.
Q: What is the molecular activity of the DUP/COS family? Is "supplying ubiquitin in trans" and forming a cargo-trapping endosomal microdomain a distinct molecular function that warrants a dedicated GO term, or is it best captured as a set of biological-process and protein-clustering annotations?
Q: Under what conditions is COS9 expressed relative to its paralogs, and does the NAD+/Sir2-dependent subtelomeric derepression that induces the COS family apply equally to COS9 given its chromosome XI location?
Experiment: Construct a chromosomally tagged Cos9 (e.g. Cos9-GFP) strain and assay steady-state localization and vacuolar sorting, alongside ubiquitination-site mapping, to establish whether Cos9 behaves like the characterized Cos5.
Hypothesis: Cos9 localizes to endosomes, is ubiquitinated by the Rsp5 system, and is itself sorted into the vacuole, matching the family behavior established for Cos5.
Experiment: Delete COS9 individually and in a COS-family-sensitized background (e.g. combined with single deletions of other COS genes and/or sna3Ξ bsd2Ξ) and quantify MVB sorting of reporter cargoes (Mup1-GFP, Ste3-GFP, GPI-anchored YFP fusions) to measure Cos9's individual contribution to cargo sorting.
Hypothesis: COS9 contributes redundantly to MVB cargo sorting; its loss produces a measurable defect only when other COS family members are also compromised.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether COS9 is functionally equivalent to the characterized paralog COS5 (i.e. an active, redundant MVB-sorting factor) or is instead specialized, expressed only under particular conditions, or effectively dispensable, is undetermined. All functional annotations of COS9 are homology-based (ISS from COS5); no COS9-specific loss-of-function or localization experiment has been reported.
OPEN BIOLOGY BP_DARK
What is known: COS9 (YKL219W) is a subtelomeric DUP/COS-family multi-pass membrane protein. The COS family (COS1-COS10, COS12) is highly similar at protein and nucleotide level and shows strong functional redundancy β a phenotype required deletion of all COS genes together. The endosome and MVB-sorting annotations on COS9 are transferred by ISS from COS5, the experimentally studied representative; COS9 itself was not among the individually tested genes (COS1, COS2, COS4, COS5, COS6).
Significance: Subtelomeric multigene families such as COS are a common source of "dark," redundant paralogs whose individual roles are rarely dissected. Establishing whether COS9 is an active member, a conditionally expressed variant, or a near-pseudogene would sharpen the annotation of the whole family and of yeast MVB sorting.
What would resolve it: COS9-specific expression profiling across growth/nutrient-stress conditions; a COS9-tagged strain to test endosomal localization directly; and single-gene deletion in a COS-family-sensitized background with cargo-sorting assays to measure COS9's individual contribution.
Provenance (the field's own admissions):
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