sil1 (systematic name SPAC1071.03c; UniProt Q9UTR0) is the Schizosaccharomyces pombe member of the SIL1/HspBP1 family of nucleotide-exchange factors (NEFs) for Hsp70 chaperones. It is the one-to-one ortholog of human SIL1 (the gene mutated in Marinesco-Sjogren syndrome) and of Saccharomyces cerevisiae Sil1p/YOL031C. The 338-residue protein is built around an armadillo-repeat (ARM-type) alpha-helical fold, the structural hallmark of this NEF class, and carries an N-terminal hydrophobic segment (residues ~20-42) that is most consistent with an endoplasmic-reticulum signal/anchor sequence. By orthology, Sil1-family proteins act in the endoplasmic reticulum, where they bind the ATPase (nucleotide-binding) domain of the ER Hsp70 chaperone BiP (Kar2p in budding yeast) and accelerate ADP release, thereby driving the BiP chaperone cycle that folds and translocates nascent secretory proteins. In budding yeast BiP is served by two functionally distinct NEFs, Sil1p and the Hsp110/Grp170-type Lhs1p; either single deletion is viable but the double deletion is lethal, indicating that BiP nucleotide exchange is essential and partly redundant. In fission yeast sil1 is non-essential (deletion viable) and has not been characterized biochemically; the molecular NEF activity, ER localization, and biological roles above are inferred from conserved domain architecture and orthology rather than from direct experiments in this species.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: Endoplasmic reticulum is the expected site of action for a SIL1-family BiP nucleotide-exchange factor. The IBA (phylogenetic) inference is consistent with the ER-lumenal localization of the S. cerevisiae and human orthologs and with the N-terminal ER signal/anchor sequence of the pombe protein. This is the meaningful, informative compartment for the gene and is retained as the core localization. Direct localization data in fission yeast are not available. |
| GO:0000774 adenyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is the defining molecular function of the SIL1/HspBP1 family: binding the ATPase (nucleotide-binding) domain of an ER Hsp70 (BiP/Kar2p) and stimulating ADP release (nucleotide exchange). It is well supported by orthology to experimentally characterized S. cerevisiae Sil1p and human SIL1, and by the diagnostic armadillo-repeat fold. This is a specific, informative MF term (preferable to generic protein binding) and is retained as the core function. The activity has not been demonstrated biochemically in S. pombe itself. Supporting Evidence: PMID:20430899 These studies identified a role for the IIB domain of Kar2p in Sil1p binding and Sil1p-stimulated nucleotide exchange |
| GO:0016020 membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: This IEA annotation is an automatic mapping from the UniProt Subcellular Location keyword (SL-0162 Membrane), which itself derives from a single predicted N-terminal transmembrane/hydrophobic segment (residues ~20-42). For a SIL1-family protein this hydrophobic stretch is more consistent with an ER signal/anchor than with a genuine multi-compartment membrane residence, and generic membrane is uninformative relative to the endoplasmic reticulum term already annotated. Retained as a non-core, low-information electronic annotation. |
| GO:0006616 SRP-dependent cotranslational protein targeting to membrane, translocation | ISO GO_REF:0000024 | KEEP AS NON CORE | Summary: This ISO annotation was transferred from a S. cerevisiae ortholog (SGD:S000005391) and reflects the participation of the BiP/Kar2p chaperone system in translocation of nascent secretory polypeptides into the ER. It is a downstream, process-level attribution of the Sil1 NEF role (Sil1 assists BiP, which acts in ER protein import) rather than sil1's core molecular function, and it is not directly demonstrated in fission yeast. The essence of ER-protein-biogenesis involvement is defensible, so it is kept as non-core rather than removed; the precise process term is broader than what is established for sil1 specifically in pombe. |
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Download this section (compressed HTML)Q: Does S. pombe Sil1 bind fission-yeast BiP and stimulate its nucleotide exchange, as its orthologs do for Kar2p and mammalian BiP?
Suggested experts: ER chaperone / Hsp70 co-chaperone biochemists, Fission-yeast secretory-pathway biologists
Q: Is sil1 functionally redundant with the pombe Hsp110/Grp170-type BiP NEF, such that the double deletion is synthetically lethal as in budding yeast?
Suggested experts: Yeast ER-proteostasis geneticists
Experiment: Reconstitute recombinant pombe Sil1 with pombe BiP and measure Sil1-stimulated nucleotide exchange and ATPase activity to test the inferred NEF function directly.
Type: In-vitro biochemistry
Experiment: Build sil1 single and sil1 plus Lhs1/Grp170-ortholog double deletions and test for synthetic lethality and ER-stress (tunicamycin, DTT) hypersensitivity to define redundancy among pombe BiP NEFs.
Type: Genetic interaction analysis
Experiment: Determine the subcellular localization and membrane topology of tagged pombe Sil1 (ER lumen vs membrane; protease protection) to resolve the single-pass-membrane vs lumenal ambiguity.
Type: Localization / topology
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Whether Sil1 nucleotide-exchange activity is individually required in S. pombe, or is functionally redundant with the fission-yeast Hsp110/Grp170-type NEF (the Lhs1/Grp170 class), is undetermined; the phenotypic consequence of losing sil1 versus losing both BiP NEFs has not been tested in pombe.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: In S. cerevisiae, single sil1 or lhs1 deletions are viable but the sil1 lhs1 double deletion is lethal, showing the two NEFs are partly redundant and that BiP nucleotide exchange is essential. In S. pombe, sil1 deletion is viable, but no analogous single/double NEF-deletion analysis has been reported.
Significance: Determines whether sil1 is a dispensable, redundant NEF in pombe or contributes a non-redundant function, and whether the conserved "BiP has two NEFs, together essential" logic holds in fission yeast.
What would resolve it: Construct and phenotype pombe sil1 single and sil1 (Lhs1/Grp170-ortholog) double deletions for synthetic lethality and ER-stress sensitivity.
Provenance (the field's own admissions):
Gap: The in-vivo biological roles and physiological clients of sil1 in S. pombe are unknown; the only pombe phenotypes are scattered drug/stress sensitivities and a cell-fusion morphology defect drawn from genome-wide screens, none mechanistically connected to its BiP-NEF activity.
OPEN BIOLOGY BP_DARK
What is known: sil1 deletion is viable with grossly normal morphology; genome-wide phenomics and a mating-morphology screen recorded assorted stress phenotypes and an "incomplete cell wall disassembly at cell fusion site" phenotype, but there is no dedicated study of sil1 in fission yeast.
Significance: Whether sil1 has a specialized secretory/ER-proteostasis role in pombe (e.g. in mating or cell-wall remodeling) beyond generic BiP support is unresolved.
What would resolve it: Directed phenotyping of sil1 deletion under ER stress (tunicamycin, DTT) and mating conditions, and identification of Sil1/BiP-dependent secretory cargo by proteomics.
Provenance (the field's own admissions):
Gap: The membrane topology and ER-retention mechanism of pombe Sil1 are unresolved: the protein is annotated as a single-pass membrane protein from one predicted TM helix, yet SIL1-family orthologs are ER-lumenal, and no canonical HDEL/KDEL retention motif is evident in the pombe sequence.
OPEN BIOLOGY CC_DARK
What is known: UniProt/TMHMM predict one hydrophobic segment at residues ~20-42 and an ECO:0000305 single-pass membrane call; S. cerevisiae Sil1p and human SIL1 are ER-lumenal with signal and ER-retention signals. The actual topology of the pombe protein has not been determined experimentally.
Significance: Clarifies whether the N-terminal hydrophobic segment is a signal/anchor for an ER-lumenal NEF (as in orthologs) and how the protein is retained in the ER.
What would resolve it: Determine subcellular localization and topology (protease-protection, lumenal vs membrane fractionation, tagged-protein imaging) of pombe Sil1.
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