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. Nsg1 also acts at the nucleus-vacuole junction during glucose-starvation control of HMG-CoA reductases: glucose-starvation remodeling destabilizes Nsg1 and thereby activates Hmg1, while Nsg2 is stabilized and suppresses Hmg1 to fine-tune sterol synthesis.
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. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000393022 · PTN000393022 SUPPORTS TRANSFER This INSIG-family PAINT node correctly propagates ER localization to yeast Nsg1, whose ER-membrane localization is directly supported. |
| GO:0016126 sterol biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: NSG1 participates in sterol biosynthetic control by acting on the sterol-pathway HMG-CoA reductases rather than by catalyzing a sterol biosynthetic reaction itself. Reason: Retained as pathway participation rather than modified to a regulation term because Nsg1 acts on the HMG-CoA reductases themselves: it binds and stabilizes the sterol-sensing-domain client Hmg2 and the newer glucose-starvation evidence ties Nsg1/Nsg2 remodeling directly to Hmg1 activity and squalene accumulation. The inherited broad pathway term does not require NSG1 to catalyze a sterol biosynthetic reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000393022 · PTN000393022 SUPPORTS TRANSFER This INSIG-family PAINT node correctly propagates participation in sterol biosynthetic pathway control; yeast Nsg1 itself has direct Hmg2-stabilization evidence, so its presence among the descendant evidence is expected rather than circular. 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. | REMOVE | Summary: The Hmg2 interaction is the correct NSG1 client evidence, but GO:0005515 protein binding is a generic proxy for the sterol-sensing domain chaperone mechanism. Reason: The supporting entity is the functional client Hmg2 (UniProtKB:P12684). Removing this uninformative GO:0005515 row does not discard that Hmg2 interaction; the specific activity is captured by the GO:0044183 protein folding chaperone replacement and the proposed sterol-sensing domain protein chaperone term. |
| GO:0005515 protein binding | IPI PMID:27107014 An inter-species protein-protein interaction network across ... | REMOVE | Summary: This human KASH5 cross-species interactome hit does not establish a yeast NSG1 molecular function. Reason: The supporting entity is human KASH5 (UniProtKB:Q8N6L0) from a cross-species interactome study and is flagged Xeno in the UniProt NSG1 record. This row should not be converted into a yeast Hmg2 mechanism; the only action needed is removal of the uninformative GO:0005515 assertion. |
| GO:0005515 protein binding | IPI PMID:37968396 The social and structural architecture of the yeast protein ... | REMOVE | Summary: The Hmg2 interaction is the correct NSG1 client evidence, but GO:0005515 protein binding is a generic proxy for the sterol-sensing domain chaperone mechanism. Reason: The supporting entity is the functional client Hmg2 (UniProtKB:P12684). Removing this uninformative GO:0005515 row does not discard that Hmg2 interaction; the specific activity is captured by the GO:0044183 protein folding chaperone replacement and the proposed sterol-sensing domain protein chaperone term. |
| 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; the 2026 glucose-starvation study independently supports recruitment of Nsg1 and Nsg2 to the NVJ with Hmg1 and Hmg2. 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. PMID:42227952 Here, we identify the aspartyl protease Ypf1 and the yeast INSIG homologs Nsg1 and Nsg2 as NVJ-localized proteins specifically recruited during GS. |
| 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 participates in sterol biosynthetic control by stabilizing the Hmg2 HMG-CoA reductase rather than by catalyzing a sterol biosynthetic reaction itself. Reason: Retained as pathway participation rather than modified to a regulation term because the genetic evidence in this row is anchored on NSG1 control of the Hmg2 HMG-CoA reductase itself, rather than a distant or pleiotropic sterol phenotype. 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 participates in sterol biosynthetic control by stabilizing the Hmg2 HMG-CoA reductase rather than by catalyzing a sterol biosynthetic reaction itself. Reason: Retained as pathway participation rather than modified to a regulation term because the interaction evidence in this row connects Nsg1 to the Hmg2 HMG-CoA reductase itself, rather than to a distant or pleiotropic sterol phenotype. 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. |
| GO:0006457 protein folding | IEA GO_REF:0000108 | ACCEPT | Summary: Protein folding is a broad but valid logical consequence of NSG1 protein folding chaperone activity toward the Hmg2 sterol-sensing domain. Reason: The live GOA row is inferred from GO:0044183 protein folding chaperone; NSG1 stabilizes Hmg2 through a direct sterol-sensing-domain interaction, so the broad process inference is faithful to the accepted molecular function. Supporting Evidence: PMID:16270032 Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. |
| GO:0031965 nuclear membrane | IDA PMID:42227952 Glucose starvation signaling via nucleus-vacuole junction re... | KEEP AS NON CORE | Summary: The 2026 glucose-starvation study places NSG1 at the nuclear membrane/NVJ under starvation, but this is a conditional localization rather than NSG1's primary Hmg2-chaperone role. Reason: SGD curated this nuclear membrane IDA row from the full 2026 paper, and the cached abstract independently reports glucose-starvation recruitment of Nsg1/Nsg2/Hmg1/Hmg2 to the NVJ in association with nuclear-membrane lipid remodeling. Keep the localization as supported but non-core relative to the constitutive ER-membrane Hmg2 stabilization function. Supporting Evidence: PMID:42227952 Ypf1 promotes the recruitment of Nsg1, Nsg2, and the HMG-CoA reductases Hmg1 and Hmg2 to the NVJ, likely in association with changes in nuclear membrane lipid composition caused by suppression of fatty acid elongases. |
| GO:0044183 protein folding chaperone | IMP PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | ACCEPT | Summary: NSG1 acts as an INSIG-family protein folding chaperone for the sterol-sensing-domain-containing Hmg2 HMG-CoA reductase. Reason: The current SGD row is the direct protein folding chaperone replacement for the old GO:0051082 row. The Hmg2 stability phenotype is tied to direct interaction with Hmg2's sterol-sensing-domain transmembrane region. 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. |
| GO:0044183 protein folding chaperone | IPI PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | ACCEPT | Summary: NSG1 acts as an INSIG-family protein folding chaperone for its direct interactor and client Hmg2. Reason: The IPI-supported GO:0044183 row captures the same Hmg2 interaction that previously underlay the now-retired GO:0051082 binding row, but uses an activity term that better reflects Nsg1 stabilization of the Hmg2 sterol-sensing-domain region. Supporting Evidence: PMID:16270032 Yeast Nsgs inhibit degradation of Hmg2p in a highly specific manner, by directly interacting with the sterol-sensing domain (SSD)-containing transmembrane region. |
| GO:0071561 nucleus-vacuole junction | IDA PMID:42227952 Glucose starvation signaling via nucleus-vacuole junction re... | KEEP AS NON CORE | Summary: NSG1 is recruited to the nucleus-vacuole junction during glucose starvation as part of a sterol-regulatory remodeling response. Reason: The 2026 study adds independent IDA evidence for glucose-starvation NVJ localization. This confirms a conditional contact-site pool while leaving Hmg2 stabilization at the ER membrane as the core molecular role. Supporting Evidence: PMID:42227952 Here, we identify the aspartyl protease Ypf1 and the yeast INSIG homologs Nsg1 and Nsg2 as NVJ-localized proteins specifically recruited during GS. |
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Download this section (compressed HTML)Q: How does glucose-starvation NVJ remodeling destabilize Nsg1 while stabilizing Nsg2?
Q: Which client-specific determinants make Nsg1 restrain Hmg1 under glucose starvation while stabilizing Hmg2 during glucose-replete sterol control?
Experiment: Combine live-cell NSG1/Hmg1/Hmg2/NVJ marker imaging with reductase stability assays in glucose-replete and glucose-restricted cells, using NSG1 mutants that disrupt Hmg2 binding or NVJ enrichment.
Hypothesis: NSG1 NVJ recruitment modulates Hmg1/Hmg2 stability or sterol storage during glucose limitation.
Type: live-cell fluorescence microscopy with cycloheximide-chase protein stability assay
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Download this section (compressed HTML)Protein involved in regulation of sterol biosynthesis; stabilizes Hmg2p, one of two HMG-CoA isoenzymes that catalyze the rate-limiting step in sterol biosynthesis; localizes to the nucleus and ER; localizes to the nucleus-vacuole junction during glucose restriction; forms foci at the nuclear periphery upon DNA replication stress; relocalizes to the cytosol in response to hypoxia; homolog of mammalian INSIG proteins; NSG1 has a paralog, NSG2, that arose from the whole genome duplication
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