NSG1 encodes an INSIG-family multi-pass endoplasmic reticulum membrane protein that binds the sterol-sensing-domain-containing Hmg2 HMG-CoA reductase and stabilizes it against Hrd1-dependent ER-associated degradation. Its primary role is a selective transmembrane chaperone/regulator of Hmg2 stability in sterol pathway control; recent microscopy also supports condition-dependent residence at the nucleus-vacuole junction, but that localization is secondary to the Hmg2 quality-control function.
Definition: Binding to and stabilizing the transmembrane sterol-sensing domain of a client protein to promote correct folding or prevent ER-associated degradation.
Justification: NSG1/INSIG activity toward Hmg2 is more specific than generic unfolded protein binding or broad protein folding chaperone activity.
Parent term: protein folding chaperone
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: endoplasmic reticulum is consistent with NSG1 being a multi-pass ER membrane INSIG homolog. Reason: Direct UniProt/literature evidence places NSG1 at the endoplasmic reticulum membrane, where Hmg2 regulation occurs. |
| GO:0016126 sterol biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: NSG1 supports sterol biosynthesis indirectly by stabilizing Hmg2, a sterol-pathway HMG-CoA reductase isozyme, rather than by catalyzing a sterol biosynthetic reaction. Reason: Accept as a pathway participation annotation with the mechanism explicitly interpreted as Hmg2 stabilization/regulation; PANTHER family transfer is consistent with the direct yeast Hmg2 evidence. Supporting Evidence: PMID:16270032 We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. file:yeast/NSG1/NSG1-deep-research-falcon.md Primary function is **stabilization of the Hmg2 HMGR isozyme** |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: endoplasmic reticulum membrane is consistent with NSG1 being a multi-pass ER membrane INSIG homolog. Reason: Direct UniProt/literature evidence places NSG1 at the endoplasmic reticulum membrane, where Hmg2 regulation occurs. |
| GO:0005515 protein binding | IPI PMID:18467557 An in vivo map of the yeast protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic protein binding annotations from interactome studies do not capture the specific NSG1/Hmg2 sterol-sensing-domain chaperone mechanism. Reason: The defensible NSG1 function is selective stabilization of SSD-containing Hmg2, not unspecific protein binding from high-throughput PPI evidence. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding annotations from interactome studies do not capture the specific NSG1/Hmg2 sterol-sensing-domain chaperone mechanism. Reason: The defensible NSG1 function is selective stabilization of SSD-containing Hmg2, not unspecific protein binding from high-throughput PPI evidence. |
| GO:0005515 protein binding | IPI PMID:37968396 The social and structural architecture of the yeast protein ... | MARK AS OVER ANNOTATED | Summary: Generic protein binding annotations from interactome studies do not capture the specific NSG1/Hmg2 sterol-sensing-domain chaperone mechanism. Reason: The defensible NSG1 function is selective stabilization of SSD-containing Hmg2, not unspecific protein binding from high-throughput PPI evidence. |
| GO:0071561 nucleus-vacuole junction | IDA PMID:41132095 Role of Pex31 in metabolic adaptation of the nucleus-vacuole... | KEEP AS NON CORE | Summary: NSG1 is detected at the nucleus-vacuole junction under glucose limitation, but this is a conditional localization rather than the primary mechanistic function. Reason: Keep as a supported context-specific localization from the 2025 NVJ remodeling study, while not elevating it over the ER/Hmg2 core function. Supporting Evidence: PMID:41132095 Here, we used systematic microscopy-based approaches to compare the NVJ at glucose-replete and -restricted conditions and identified five additional NVJ proteins: the permanent NVJ resident Shr5 and the conditional residents Nsg1, Nsg2, Tcb1 and Pex31. |
| GO:0005783 endoplasmic reticulum | HDA PMID:26928762 One library to make them all: streamlining the creation of y... | ACCEPT | Summary: endoplasmic reticulum is consistent with the ER biology of NSG1 and is supported by the SWAT endomembrane localization library. Reason: Accept as supporting ER localization evidence, with gene-specific ER function anchored by the primary literature and UniProt record. Supporting Evidence: PMID:26928762 we constructed and investigated a library of |
| GO:0034399 nuclear periphery | HDA PMID:22842922 Dissecting DNA damage response pathways by analysing protein... | KEEP AS NON CORE | Summary: Nuclear periphery localization is compatible with ER/nuclear-envelope contact-site biology but is not the defining NSG1 function. Reason: Retain as non-core localization context, especially given independent NVJ/nuclear-ER evidence, but core function remains Hmg2 stabilization at ER membranes. |
| GO:0005829 cytosol | IDA PMID:22932476 The nuclear localization of SWI/SNF proteins is subjected to... | MARK AS OVER ANNOTATED | Summary: cytosol is not well aligned with NSG1 as a multi-pass ER membrane protein and likely reflects screen/context-specific signal rather than a stable functional location. Reason: The stronger direct evidence supports ER membrane and conditional NVJ/nuclear-ER localization; soluble cytosol/nucleus annotations overstate the localization of this membrane protein. |
| GO:0005634 nucleus | IDA PMID:22932476 The nuclear localization of SWI/SNF proteins is subjected to... | MARK AS OVER ANNOTATED | Summary: nucleus is not well aligned with NSG1 as a multi-pass ER membrane protein and likely reflects screen/context-specific signal rather than a stable functional location. Reason: The stronger direct evidence supports ER membrane and conditional NVJ/nuclear-ER localization; soluble cytosol/nucleus annotations overstate the localization of this membrane protein. |
| GO:0005783 endoplasmic reticulum | IDA PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | ACCEPT | Summary: endoplasmic reticulum is consistent with NSG1 being a multi-pass ER membrane INSIG homolog. Reason: Direct UniProt/literature evidence places NSG1 at the endoplasmic reticulum membrane, where Hmg2 regulation occurs. Supporting Evidence: PMID:16270032 by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region |
| GO:0016126 sterol biosynthetic process | IMP PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | ACCEPT | Summary: NSG1 supports sterol biosynthesis indirectly by stabilizing Hmg2, a sterol-pathway HMG-CoA reductase isozyme, rather than by catalyzing a sterol biosynthetic reaction. Reason: Accept as a pathway participation annotation with the mechanism explicitly interpreted as Hmg2 stabilization/regulation; PANTHER family transfer is consistent with the direct yeast Hmg2 evidence. Supporting Evidence: PMID:16270032 We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. |
| GO:0016126 sterol biosynthetic process | IPI PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | ACCEPT | Summary: NSG1 supports sterol biosynthesis indirectly by stabilizing Hmg2, a sterol-pathway HMG-CoA reductase isozyme, rather than by catalyzing a sterol biosynthetic reaction. Reason: Accept as a pathway participation annotation with the mechanism explicitly interpreted as Hmg2 stabilization/regulation; PANTHER family transfer is consistent with the direct yeast Hmg2 evidence. Supporting Evidence: PMID:16270032 We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. |
| GO:0051082 unfolded protein binding | IMP PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | MODIFY | Summary: The Hmg2 stabilization evidence supports a chaperone-like activity, but unfolded protein binding is too generic for the INSIG/SSD-client mechanism. Reason: Replace with protein folding chaperone pending a more specific sterol-sensing-domain chaperone term. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:16270032 We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. |
| GO:0051082 unfolded protein binding | IPI PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | MODIFY | Summary: The Hmg2 stabilization evidence supports a chaperone-like activity, but unfolded protein binding is too generic for the INSIG/SSD-client mechanism. Reason: Replace with protein folding chaperone pending a more specific sterol-sensing-domain chaperone term. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:16270032 We now show that the yeast INSIG homologs NSG1 and NSG2 function to control the stability of yeast Hmg2p, the HMGR isozyme that undergoes regulated ubiquitination. Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. |
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Download this section (compressed HTML)Q: Does NSG1 have a direct Hmg2-independent role at the nucleus-vacuole junction in sterol storage or lipid-transfer adaptation, or is NVJ enrichment mainly a relocalization of the Hmg2 regulatory module?
Experiment: Combine live-cell NSG1/Hmg2/NVJ marker imaging with Hmg2 stability assays in glucose-replete and glucose-restricted cells, using NSG1 mutants that disrupt Hmg2 binding or NVJ enrichment.
Hypothesis: NSG1 NVJ recruitment modulates Hmg2 stabilization or sterol storage during glucose limitation.
Type: live-cell fluorescence microscopy with cycloheximide-chase protein stability assay
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