NSG2 encodes a multi-pass endoplasmic-reticulum membrane INSIG-family protein. Together with the paralog Nsg1, Nsg2 regulates sterol homeostasis by interacting with sterol-sensing-domain-containing HMG-CoA reductase proteins, especially Hmg2, and limiting HRD-dependent ER-associated degradation. Nsg1 is the dominant native stabilizer in the classic Hmg2 assays, but Nsg2 can stabilize Hmg2 when overexpressed and contributes in Nsg1-deficient contexts. During glucose-starvation remodeling, Nsg2 is recruited to the nucleus-vacuole junction and stabilized there, where it 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: Nsg2 and related Nsg/INSIG-family proteins interact directly with the sterol-sensing-domain-containing transmembrane region of Hmg2 and inhibit its HRD-dependent degradation. GO:0044183 protein folding chaperone is the closest available molecular-function parent but overemphasizes de novo folding, GO:1904293 negative regulation of ERAD pathway captures the downstream process rather than the activity, and GO:0050821 protein stabilization likewise captures the outcome rather than SSD-client binding specificity.
Parent term: protein folding chaperone
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: PANTHER/IBA transfer to endoplasmic reticulum is consistent with the INSIG family context and with direct experimental localization of Nsg proteins to ER membranes. Reason: NSG2 is an INSIG-family multi-pass ER membrane protein. The family-transfer annotation is appropriate and agrees with focused evidence from the yeast NSG/Hmg2 literature. 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 Nsg2, an experimentally supported multi-pass ER membrane INSIG-family protein; the IBD node is scoped to Opisthokonta and includes budding yeast. Supporting Evidence: UniProt:P53898 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass membrane protein. |
| GO:0016126 sterol biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: The PANTHER/IBA sterol biosynthetic process annotation is consistent with the conserved INSIG-family role in regulating sterol-pathway HMG-CoA reductase stability. Reason: NSG2 should not be interpreted as a sterol biosynthetic enzyme. Its role is regulatory/chaperone-like, acting through Hmg2 stability and sterol-sensing domain client interactions. The process annotation remains appropriate because this regulatory function affects sterol biosynthesis. 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 Nsg2 itself has descendant experimental evidence in PAINT for the same term, which supports node placement rather than making the IBA circular. The IBD node is scoped to Opisthokonta; PAINT separately assigns mammalian cholesterol-biosynthesis regulation to a Eumetazoa node, consistent with the inverted direction of regulated HMGR degradation between yeast and mammals. 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. file:yeast/NSG2/NSG2-deep-research-falcon.md NSG2 functions in sterol/ergosterol homeostasis and regulated ER-associated degradation of Hmg2. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to ER membrane is consistent with NSG2's experimentally supported INSIG-family membrane protein identity. Reason: ER membrane is the core compartment for Nsg2 regulation of Hmg2 stability. Supporting Evidence: UniProt:P53898 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass membrane protein. |
| GO:0071561 nucleus-vacuole junction | IDA PMID:41132095 Role of Pex31 in metabolic adaptation of the nucleus-vacuole... | KEEP AS NON CORE | Summary: Direct microscopy evidence identifies Nsg2 as a nucleus-vacuole junction resident under low-glucose conditions. Reason: The NVJ annotation is valid but context-dependent. It should be retained as a starvation/contact-site localization without replacing ER membrane as the core site for the classic Hmg2 stability function. PMID:41132095 places both Nsg1 and Nsg2 at the NVJ as conditional residents, while PMID:42227952 adds a paralog-specific outcome: glucose-starvation remodeling destabilizes Nsg1 but stabilizes Nsg2, which suppresses Hmg1 to fine-tune sterol synthesis. Supporting Evidence: PMID:41132095 We identified Pex31, Nsg1, Nsg2, Shr5, and Tcb1 as NVJ residents. PMID:41132095 Nsg1, Nsg2 and Tcb1 belong to the large group of conditional NVJ residents that accumulate at low-glucose conditions 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:0005783 endoplasmic reticulum | HDA PMID:26928762 One library to make them all: streamlining the creation of y... | ACCEPT | Summary: The high-throughput ER localization is consistent with focused evidence and the UniProt ER membrane annotation. Reason: ER localization is well aligned with NSG2's INSIG-family role in regulating ER membrane Hmg2 stability. Supporting Evidence: UniProt:P53898 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass membrane protein. |
| GO:0005783 endoplasmic reticulum | HDA PMID:14562095 Global analysis of protein localization in budding yeast | ACCEPT | Summary: The Huh et al. high-throughput localization is consistent with NSG2's ER membrane protein identity. Reason: This broad ER annotation is correct, although ER membrane is more specific. Supporting Evidence: UniProt:P53898 SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Multi-pass membrane protein. |
| GO:0016126 sterol biosynthetic process | IGI PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | ACCEPT | Summary: Genetic evidence supports NSG2 participation in sterol biosynthesis through regulation of Hmg2 stability, with partial redundancy and unequal contribution relative to NSG1. Reason: The annotation is best interpreted as a regulatory contribution to sterol biosynthesis, not as direct catalysis. The IGI evidence with NSG1/Hmg2 context is biologically coherent. 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:0051082 unfolded protein binding | IMP PMID:16270032 INSIG: a broadly conserved transmembrane chaperone for stero... | MODIFY | Summary: The evidence supports a dedicated transmembrane chaperone function for an SSD-containing client rather than broad unfolded protein binding. Reason: Nsg2 and Nsg1 interact with the Hmg2 sterol-sensing-domain-containing transmembrane region and promote Hmg2 stability/folding. GO:0044183 protein folding chaperone better captures this client-specific chaperone role than generic GO:0051082 unfolded protein binding. Proposed replacements: protein folding chaperone 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. PMID:16270032 One way to unify the known, disparate actions of INSIGs is to view them as known adaptations of a chaperone dedicated to SSD-containing client proteins. |
| GO:0006457 protein folding | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Protein folding is the live logical consequence of NSG2 protein folding chaperone activity, but it is broader than the SSD-client stabilization function shown for Hmg2. Reason: This GOA row is inferred from GO:0044183 protein folding chaperone. That molecular-function term is currently the closest available GO term for Nsg2, but the inherited protein-folding process emphasis remains overbroad for direct sterol-sensing-domain client binding that protects Hmg2 from ERAD. 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 NSG2 at the nuclear membrane/NVJ under starvation, but this is a conditional localization rather than the primary ER/Hmg2 chaperone context. 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: NSG2 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:0071561 nucleus-vacuole junction | IDA PMID:42227952 Glucose starvation signaling via nucleus-vacuole junction re... | KEEP AS NON CORE | Summary: NSG2 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 and specifically links stabilized Nsg2 to Hmg1 suppression. This confirms a conditional contact-site pool while leaving Hmg2 stabilization at the ER membrane as the classic 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. |
Loading supporting content…
Download this section (compressed HTML)Q: What client specificity distinguishes Nsg2 from Nsg1 at native expression levels, and which HMG-CoA reductase isozyme or sterol-sensing-domain clients require Nsg2 specifically?
Q: Does stabilized Nsg2 suppress Hmg1 at the nucleus-vacuole junction by directly binding the Hmg1 sterol-sensing domain, by changing Hmg1 assembly, or indirectly through local nuclear-membrane lipid composition?
Q: What structural or membrane-composition cues cause glucose-starvation NVJ remodeling to stabilize Nsg2 while destabilizing the paralogous Nsg1?
Experiment: Compare Hmg1 and Hmg2 stability, ERAD flux, and sterol intermediate levels in nsg1, nsg2, and nsg1 nsg2 mutants under sterol-replete, sterol-depleted, and low-glucose conditions.
Type: genetics
Experiment: Map Nsg2 client contacts by crosslinking or co-immunoprecipitation of functional tagged Nsg2 with Hmg1/Hmg2 SSD-domain mutants.
Type: biochemistry
Experiment: Quantify Nsg2 recruitment to the NVJ during glucose starvation and test whether disrupting NVJ tethering changes sterol ester, squalene, or HMG-CoA reductase activity phenotypes.
Type: microscopy
Loading supporting content…
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 ER; localizes to the nucleus-vacuole junction during glucose restriction; homolog of mammalian INSIG proteins; NSG2 has a paralog, NSG1, that arose from the whole genome duplication
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)