INSIG1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005515 protein binding	IPI PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	MODIFY	Summary: Sterol-dependent binding of INSIG1 to SCAP (UniProtKB:P97260), the interaction that holds SCAP-SREBP in the ER. Reason: The interaction is real and is the core mechanism of this protein, but protein binding is uninformative. Binding to sterol-loaded SCAP prevents COPII from engaging SCAP and keeps SCAP-SREBP in the ER, which is what GO:0140311 protein sequestering activity describes; that term is already supported by IDA rows for this gene and by GO-CAM 6205c24300000880. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Proposed replacements: protein sequestering activity Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER PMID:12202038 Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER.
GO:0005515 protein binding	IPI PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ...	MODIFY	Summary: Sterol-dependent binding of INSIG1 to SCAP (UniProtKB:P97260), the interaction that holds SCAP-SREBP in the ER. Reason: The interaction is real and is the core mechanism of this protein, but protein binding is uninformative. Binding to sterol-loaded SCAP prevents COPII from engaging SCAP and keeps SCAP-SREBP in the ER, which is what GO:0140311 protein sequestering activity describes; that term is already supported by IDA rows for this gene and by GO-CAM 6205c24300000880. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Proposed replacements: protein sequestering activity Supporting Evidence: PMID:15899885 This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells.
GO:0005515 protein binding	IPI PMID:16168377 Gp78, a membrane-anchored ubiquitin ligase, associates with ...	MODIFY	Summary: INSIG1 binds AMFR/gp78; INSIG1 links the gp78 E3 ligase to sterol-loaded HMGCR during sterol-accelerated ERAD. Reason: Protein binding is uninformative. In these studies INSIG1 bridges the membrane E3 gp78/AMFR (with VCP) and its substrate HMGCR (and, later work showed, ACAT2/SOAT2), so the informative molecular function is GO:1990756 ubiquitin-like ligase-substrate adaptor activity. The cached copies are abstract-only, but the abstracts state the bridging role directly. INSIG2 receives the same MF as NEW, based on its TRC8-dependent role (PMID:22143767); gp78 binds INSIG1 but not INSIG2, so only INSIG1 carries gp78 binding rows. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:16168377 Insig-1 as a bridge between gp78/VCP and the reductase substrate PMID:16168377 we show that gp78, a membrane bound E3, binds to Insig-1 and is required for sterol-regulated ubiquitination of reductase PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0005515 protein binding	IPI PMID:21081644 Progesterone receptor membrane component 1 inhibits the acti...	REMOVE	Summary: Binding of INSIG1 to a rabbit cytochrome P450 (UniProtKB:P00180) reported in a PGRMC1/P450 study. Reason: Generic protein binding is uninformative. The interaction is not disputed, but the paper concluded that INSIG1 and PGRMC1 act independently on P450, so it supports no specific INSIG1 molecular function. Removal is of the uninformative term, not a claim that the interaction is false. Supporting Evidence: PMID:21081644 INSIG1, which binds to both PGRMC1 and P450, was a potential intermediary protein, but our results suggest that INSIG1 and PGRMC1 act independently on P450.
GO:0005515 protein binding	IPI PMID:21081644 Progesterone receptor membrane component 1 inhibits the acti...	REMOVE	Summary: Binding of INSIG1 to a rabbit cytochrome P450 (UniProtKB:P00181) reported in a PGRMC1/P450 study. Reason: Generic protein binding is uninformative. The interaction is not disputed, but the paper concluded that INSIG1 and PGRMC1 act independently on P450, so it supports no specific INSIG1 molecular function. Removal is of the uninformative term, not a claim that the interaction is false. Supporting Evidence: PMID:21081644 INSIG1, which binds to both PGRMC1 and P450, was a potential intermediary protein, but our results suggest that INSIG1 and PGRMC1 act independently on P450.
GO:0005515 protein binding	IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78...	MODIFY	Summary: INSIG1 binds HMGCR (hamster); INSIG1 links the gp78 E3 ligase to sterol-loaded HMGCR during sterol-accelerated ERAD. Reason: Protein binding is uninformative. In these studies INSIG1 bridges the membrane E3 gp78/AMFR (with VCP) and its substrate HMGCR (and, later work showed, ACAT2/SOAT2), so the informative molecular function is GO:1990756 ubiquitin-like ligase-substrate adaptor activity. The cached copies are abstract-only, but the abstracts state the bridging role directly. INSIG2 receives the same MF as NEW, based on its TRC8-dependent role (PMID:22143767); gp78 binds INSIG1 but not INSIG2, so only INSIG1 carries gp78 binding rows. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:21343306 mediates sterol-accelerated ERAD of the cholesterol biosynthetic enzyme HMG-CoA reductase PMID:28604676 Insigs work as adaptors to recruit substrates including ACAT2 and HMGCR PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0005515 protein binding	IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78...	MODIFY	Summary: INSIG1 binds AMFR/gp78; INSIG1 links the gp78 E3 ligase to sterol-loaded HMGCR during sterol-accelerated ERAD. Reason: Protein binding is uninformative. In these studies INSIG1 bridges the membrane E3 gp78/AMFR (with VCP) and its substrate HMGCR (and, later work showed, ACAT2/SOAT2), so the informative molecular function is GO:1990756 ubiquitin-like ligase-substrate adaptor activity. The cached copies are abstract-only, but the abstracts state the bridging role directly. INSIG2 receives the same MF as NEW, based on its TRC8-dependent role (PMID:22143767); gp78 binds INSIG1 but not INSIG2, so only INSIG1 carries gp78 binding rows. Proposed replacements: ubiquitin-like ligase-substrate adaptor activity Supporting Evidence: PMID:21343306 mediates sterol-accelerated ERAD of the cholesterol biosynthetic enzyme HMG-CoA reductase PMID:28604676 Insigs work as adaptors to recruit substrates including ACAT2 and HMGCR PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG1 with UniProtKB:Q13520. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG2 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	REMOVE	Summary: High-throughput yeast two-hybrid interaction of INSIG1 with UniProtKB:Q96Q45-2. Reason: Generic protein binding from a proteome-scale binary interactome screen. Multi-pass membrane proteins such as INSIGs give many Y2H hits with other membrane proteins, and no follow-up links this partner to INSIG function. Removed as uninformative; this does not assert that the interaction is false. The same policy is applied to the Y2H rows in the INSIG2 review. Supporting Evidence: PMID:32296183 we refer to HI-III-20 as a reference map of the human binary protein interactome (HuRI)
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	MODIFY	Summary: INSIG1 is an ER-resident protein. Reason: Correct but less specific than the evidence: INSIGs are six-transmembrane polytopic proteins of the ER membrane, and the gene already carries GO:0005789 endoplasmic reticulum membrane (IDA, IEA, TAS rows). The ER-membrane term is a part_of descendant and is what the GO-CAM model uses. Judged identically in the INSIG2 review (shared PAINT node / paralog function). For the IBA row, the node (PTN000393022) is sound; only the term granularity is refined. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000393022 SUPPORTS TRANSFER Ancestral INSIG-family node; ER residence is conserved. Only the granularity (ER vs ER membrane) is refined. SGD:S000001175 SUPPORTS TRANSFER Experimental ER localization of an extant INSIG-family member grounds the node; consistent with an integral ER membrane protein. UniProtKB:O15503 SUPPORTS TRANSFER Experimental ER localization of an extant INSIG-family member grounds the node; consistent with an integral ER membrane protein. UniProtKB:Q9Y5U4 SUPPORTS TRANSFER Experimental ER localization of an extant INSIG-family member grounds the node; consistent with an integral ER membrane protein. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:12242332 Insig-1 and -2 are both polytopic membrane proteins of the ER. file:human/INSIG1/INSIG1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005783 endoplasmic reticulum	IDA PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	MODIFY	Summary: INSIG1 is an ER-resident protein. Reason: Correct but less specific than the evidence: INSIGs are six-transmembrane polytopic proteins of the ER membrane, and the gene already carries GO:0005789 endoplasmic reticulum membrane (IDA, IEA, TAS rows). The ER-membrane term is a part_of descendant and is what the GO-CAM model uses. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER file:human/INSIG1/INSIG1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005783 endoplasmic reticulum	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	MODIFY	Summary: INSIG1 is an ER-resident protein. Reason: Correct but less specific than the evidence: INSIGs are six-transmembrane polytopic proteins of the ER membrane, and the gene already carries GO:0005789 endoplasmic reticulum membrane (IDA, IEA, TAS rows). The ER-membrane term is a part_of descendant and is what the GO-CAM model uses. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:32322062 SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. file:human/INSIG1/INSIG1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG1 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: INSIG1 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: file:human/INSIG1/INSIG1-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG1 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-NUL-2317526	ACCEPT	Summary: INSIG1 is a multi-pass membrane protein of the ER membrane, where it engages SCAP and HMGCR. Reason: Well supported: six-TM polytopic ER protein, ER distribution by immunofluorescence, and retention of SCAP-SREBP occurs in the ER membrane. This is the location of the core activities. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: Reactome:R-NUL-2317526 These interactions retain SCAP:SREBP1A/1C/2 in the endoplasmic reticulum.
GO:0006357 regulation of transcription by RNA polymerase II	NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	MARK AS OVER ANNOTATED	Summary: Regulation of RNA polymerase II transcription inferred from the effect of INSIGs on SREBP processing. Reason: INSIGs are ER membrane proteins with no nuclear role. They change SREBP target-gene transcription only indirectly, by holding SCAP-SREBP in the ER and preventing proteolytic release of the SREBP transcription factor domain. That upstream effect is captured by GO:0036316 and GO:0032933; a transcription-regulation process term overstates the participation. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis.
GO:0006695 cholesterol biosynthetic process	IBA GO_REF:0000033	MODIFY	Summary: Annotated to cholesterol biosynthetic process; INSIGs restrain, rather than carry out, cholesterol synthesis. Reason: INSIGs perform no step of cholesterol synthesis or metabolism. They lower it by retaining SCAP-SREBP in the ER (so less SREBP-driven transcription of sterol-synthesis genes) and by adapting HMGCR to ER-associated degradation. The sound essence is regulatory, with a negative sign: GO:0045541 negative regulation of cholesterol biosynthetic process. For the IBA row, the node placement (PTN001033847, vertebrate INSIGs) is not disputed, only the relation of the protein to the process. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1916289 SOURCE WEAK OR INFERRED Mouse knockout genetic evidence (IGI acts_upstream_of_or_within per QuickGO) shows necessity for normal sterol control, not that INSIG performs a biosynthetic step. MGI:MGI:1920249 SOURCE WEAK OR INFERRED Mouse knockout genetic evidence (IGI acts_upstream_of_or_within per QuickGO) shows necessity for normal sterol control, not that INSIG performs a biosynthetic step. PANTHER:PTN001033847 SUPPORTS TRANSFER Vertebrate INSIG1/INSIG2 node; the target is inside the clade and the paralogs share the function. The issue is the relation to the process (regulator, not participant), not node placement. UniProtKB:O15503 SUPPORTS SOURCE BUT NOT TARGET Human INSIG experimental row for this term; the biology supports negative regulation of cholesterol synthesis rather than participation. UniProtKB:Q9Y5U4 SUPPORTS SOURCE BUT NOT TARGET Human INSIG experimental row for this term; the biology supports negative regulation of cholesterol synthesis rather than participation. Proposed replacements: negative regulation of cholesterol biosynthetic process Supporting Evidence: PMID:12242332 By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0006695 cholesterol biosynthetic process	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	MODIFY	Summary: Annotated to cholesterol biosynthetic process; INSIGs restrain, rather than carry out, cholesterol synthesis. Reason: INSIGs perform no step of cholesterol synthesis or metabolism. They lower it by retaining SCAP-SREBP in the ER (so less SREBP-driven transcription of sterol-synthesis genes) and by adapting HMGCR to ER-associated degradation. The sound essence is regulatory, with a negative sign: GO:0045541 negative regulation of cholesterol biosynthetic process. PMID:32322062 shows that PCK1 phosphorylation of INSIG lowers sterol binding and increases lipogenesis, which again places INSIG as a negative regulator. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Proposed replacements: negative regulation of cholesterol biosynthetic process Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0008142 oxysterol binding	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG1 binds oxysterols such as 25-hydroxycholesterol, which triggers binding to SCAP. Reason: Core activity. Oxysterols act by binding to Insigs (direct binding assays, TM3/TM4 mutants), and a cryo-EM structure of human SCAP-INSIG2 shows 25-hydroxycholesterol bound between SCAP and INSIG TM3/TM4. For INSIG1, whose TM3/TM4 pocket is inferred by homology (the structure is of INSIG2), the curator's IDA from PMID:32322062 (full text not cached) is consistent with the 2007 work, which assayed Insigs generically. Accepted in both paralog reviews. Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus PMID:33446483 A 25HC molecule is sandwiched between the S4 to S6 segments in Scap and TMs 3 and 4 in Insig-2 in the luminal leaflet of the membrane. PMID:17428920 Mutational analysis of the six transmembrane helices of Insigs reveals that the third and fourth are important for Insig's binding to oxysterols and to Scap.
GO:0008203 cholesterol metabolic process	NAS PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	MODIFY	Summary: Annotated to cholesterol metabolic process; INSIGs restrain, rather than carry out, cholesterol synthesis. Reason: INSIGs perform no step of cholesterol synthesis or metabolism. They lower it by retaining SCAP-SREBP in the ER (so less SREBP-driven transcription of sterol-synthesis genes) and by adapting HMGCR to ER-associated degradation. The sound essence is regulatory, with a negative sign: GO:0045541 negative regulation of cholesterol biosynthetic process. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Proposed replacements: negative regulation of cholesterol biosynthetic process Supporting Evidence: PMID:12242332 By blocking this movement, insig-2, like the previously described insig-1, prevents the proteolytic processing of SREBPs by Golgi enzymes, thereby blocking cholesterol synthesis. PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0032869 cellular response to insulin stimulus	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Response to insulin, based on insulin-regulated expression of the INSIG genes. Reason: Insulin changes the abundance of INSIG transcripts: INSIG1 (the 'insulin-induced gene', rat CL-6) is induced, and the liver-specific Insig-2a transcript is repressed. That is regulation of the gene by insulin, not a function the INSIG protein performs in an insulin response; the opposite signs in the two paralogs also argue that no shared, inherited protein function is involved. The IBA node (PTN001033847) rests on rat Insig1, whose own row for this term is an IEP (expression) annotation, so the propagated claim inherits an expression-pattern observation rather than a functional one. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: SOURCE EVIDENCE WEAK ROLE CONFLATION Sources checked: PANTHER:PTN001033847 SOURCE WEAK OR INFERRED Node placement covers both paralogs, but its only descendant evidence for this term is an expression-pattern observation. RGD:708457 SOURCE WEAK OR INFERRED Rat Insig1 row for this term is IEP (insulin induction of the transcript), which does not show a protein function in the insulin response. Supporting Evidence: PMID:9268630 Rat CL-6 is the most highly insulin-induced gene in a liver cell line PMID:12624180 Insig-2a is the predominant transcript in livers of fed animals, and it is selectively down-regulated by insulin.
GO:0032933 SREBP signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: INSIG1 is a sterol-sensing component of the SREBP pathway that blocks SCAP-SREBP export when sterols are high. Reason: INSIGs act within the SREBP signaling pathway itself, at its first, sterol-gated step: transport of SCAP-SREBP from the ER to the Golgi. The more specific GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum is accepted as the core process; this pathway-level term still adds context and is kept. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.
GO:0032933 SREBP signaling pathway	IDA PMID:12242332 Insig-2, a second endoplasmic reticulum protein that binds S...	ACCEPT	Summary: INSIG1 is a sterol-sensing component of the SREBP pathway that blocks SCAP-SREBP export when sterols are high. Reason: INSIGs act within the SREBP signaling pathway itself, at its first, sterol-gated step: transport of SCAP-SREBP from the ER to the Golgi. The more specific GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum is accepted as the core process; this pathway-level term still adds context and is kept. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 Coexpression of insig-1 or -2 did not affect budding in the absence of sterols (lanes 4 and 6), but it permitted sterols to specifically block SCAP budding without affecting the budding of the G protein of VSV (lanes 5 and 7).
GO:0032933 SREBP signaling pathway	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG1 is a sterol-sensing component of the SREBP pathway that blocks SCAP-SREBP export when sterols are high. Reason: INSIGs act within the SREBP signaling pathway itself, at its first, sterol-gated step: transport of SCAP-SREBP from the ER to the Golgi. The more specific GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum is accepted as the core process; this pathway-level term still adds context and is kept. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum.
GO:0032937 SREBP-SCAP-Insig complex	IBA GO_REF:0000033	ACCEPT	Summary: INSIG1 forms the sterol-induced SREBP-SCAP-Insig complex in the ER membrane. Reason: The complex is defined by INSIG association with SCAP-SREBP and was detected by co-immunoprecipitation and blue native-PAGE. INSIG is a defining subunit. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.
GO:0032937 SREBP-SCAP-Insig complex	IDA PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG1 forms the sterol-induced SREBP-SCAP-Insig complex in the ER membrane. Reason: The complex is defined by INSIG association with SCAP-SREBP and was detected by co-immunoprecipitation and blue native-PAGE. INSIG is a defining subunit. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER PMID:12202038 Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER.
GO:0032937 SREBP-SCAP-Insig complex	IDA PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ...	ACCEPT	Summary: INSIG1 forms the sterol-induced SREBP-SCAP-Insig complex in the ER membrane. Reason: The complex is defined by INSIG association with SCAP-SREBP and was detected by co-immunoprecipitation and blue native-PAGE. INSIG is a defining subunit. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:15899885 This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells.
GO:0032937 SREBP-SCAP-Insig complex	NAS PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG1 forms the sterol-induced SREBP-SCAP-Insig complex in the ER membrane. Reason: The complex is defined by INSIG association with SCAP-SREBP and was detected by co-immunoprecipitation and blue native-PAGE. INSIG is a defining subunit. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER PMID:12202038 Sterols induce binding of SCAP to INSIG-1, as determined by blue native-PAGE, and this is correlated with the inhibition of SCAP exit from the ER.
GO:0036315 cellular response to sterol	IMP PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG1 is required for sterol-induced retention of SCAP-SREBP; INSIG1 overexpression sensitises cells to sterols. Reason: INSIGs are sterol sensors: oxysterol binding to INSIG, or cholesterol binding to SCAP, triggers the INSIG-SCAP interaction that shuts down SREBP processing. A cellular response to sterol is the physiological frame of the core function. The same term is proposed for INSIG2 (by MODIFY of its response to lipid IEA). Supporting Evidence: PMID:12202038 Overexpression of INSIG-1 increases the sensitivity of cells to sterol-mediated inhibition of SREBP processing. PMID:12202038 Mutant SCAP(Y298C) fails to bind INSIG-1 and is resistant to sterol-mediated inhibition of ER exit.
GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum	IBA GO_REF:0000033	ACCEPT	Summary: INSIG1 retains the SCAP-SREBP complex in the ER when sterols are present. Reason: Core process. Sterol-induced INSIG binding to SCAP prevents COPII from engaging SCAP's MELADL sorting signal, so SCAP-SREBP stays in the ER and SREBPs are not processed in the Golgi. The IBA node PTN001033847 (vertebrate INSIG1/INSIG2) is well founded on experimental data for both paralogs. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12242332 This paper describes insig-2, a second protein of the endoplasmic reticulum that blocks the processing of sterol regulatory element-binding proteins (SREBPs) by binding to SCAP (SREBP cleavage-activating protein) in a sterol-regulated fashion, thus preventing it from escorting SREBPs to the Golgi.
GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum	IDA PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG1 retains the SCAP-SREBP complex in the ER when sterols are present. Reason: Core process. Sterol-induced INSIG binding to SCAP prevents COPII from engaging SCAP's MELADL sorting signal, so SCAP-SREBP stays in the ER and SREBPs are not processed in the Golgi. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:12202038 we identify INSIG-1 as an ER protein that binds the sterol-sensing domain of SREBP cleavage-activating protein (SCAP) and facilitates retention of the SCAP/SREBP complex in the ER PMID:12202038 Mutant SCAP(Y298C) fails to bind INSIG-1 and is resistant to sterol-mediated inhibition of ER exit.
GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum	IDA PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ...	ACCEPT	Summary: INSIG1 retains the SCAP-SREBP complex in the ER when sterols are present. Reason: Core process. Sterol-induced INSIG binding to SCAP prevents COPII from engaging SCAP's MELADL sorting signal, so SCAP-SREBP stays in the ER and SREBPs are not processed in the Golgi. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:15899885 This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells. PMID:15899885 addition of cholesterol or 25-hydroxycholesterol to microsomal membranes in vitro blocks Sar1-dependent binding of the Sec23/24 complex to Scap, the SREBP escort protein
GO:0036316 SREBP-SCAP complex retention in endoplasmic reticulum	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG1 retains the SCAP-SREBP complex in the ER when sterols are present. Reason: Core process. Sterol-induced INSIG binding to SCAP prevents COPII from engaging SCAP's MELADL sorting signal, so SCAP-SREBP stays in the ER and SREBPs are not processed in the Golgi. PMID:32322062 is a single-laboratory study, but its IDA for this process agrees with earlier work. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus
GO:0042632 cholesterol homeostasis	IDA PMID:12202038 Crucial step in cholesterol homeostasis: sterols promote bin...	ACCEPT	Summary: INSIG1 contributes to cellular cholesterol homeostasis through sterol-dependent ER retention of SCAP. Reason: INSIG1 is a direct effector of sterol feedback: it couples sterol levels to SREBP activation and HMGCR degradation. Homeostasis is a broad process, but the paper's central conclusion supports it, and it is not an ancestor of the accepted specific terms. Supporting Evidence: PMID:12202038 By facilitating sterol-dependent ER retention of SCAP, INSIG-1 plays a central role in cholesterol homeostasis.
GO:0045541 negative regulation of cholesterol biosynthetic process	IDA PMID:26311497 PAQR3 modulates cholesterol homeostasis by anchoring Scap/SR...	ACCEPT	Summary: Increasing INSIG1 lowers SREBP-2 processing and sterol synthesis, opposing PAQR3. Reason: INSIGs are negative regulators of cholesterol synthesis through two routes: ER retention of SCAP-SREBP and sterol-accelerated HMGCR degradation. This is also the replacement term proposed for the cholesterol biosynthetic process rows in both paralog reviews. Supporting Evidence: PMID:26311497 increasing expression of Insig-1 reduced SREBP-2 processing PMID:12535518 degradation of HMG CoA reductase is accelerated by the sterol-induced binding of its sterol-sensing domain to the ER protein insig-1
GO:0140311 protein sequestering activity	IDA PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ...	ACCEPT	Summary: INSIG1 binds sterol-loaded SCAP and sequesters it from COPII, holding SCAP-SREBP in the ER. Reason: Core molecular function. Insig binding makes SCAP's MELADL signal inaccessible to Sec23/24, so SCAP is prevented from entering COPII vesicles. This matches the GO:0140311 definition (binding a protein to stop its localization) and the GO-CAM model 6205c24300000880. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:15899885 This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells. PMID:15899885 addition of cholesterol or 25-hydroxycholesterol to microsomal membranes in vitro blocks Sar1-dependent binding of the Sec23/24 complex to Scap, the SREBP escort protein PMID:17428919 Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig.
GO:0140311 protein sequestering activity	IDA PMID:32322062 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for li...	ACCEPT	Summary: INSIG1 binds sterol-loaded SCAP and sequesters it from COPII, holding SCAP-SREBP in the ER. Reason: Core molecular function. Insig binding makes SCAP's MELADL signal inaccessible to Sec23/24, so SCAP is prevented from entering COPII vesicles. This matches the GO:0140311 definition (binding a protein to stop its localization) and the GO-CAM model 6205c24300000880. Judged identically in the INSIG2 review (shared PAINT node / paralog function). Supporting Evidence: PMID:32322062 This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus PMID:17428919 Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig.
GO:1901303 negative regulation of cargo loading into COPII-coated vesicle	IMP PMID:15899885 Insig required for sterol-mediated inhibition of Scap/SREBP ...	ACCEPT	Summary: INSIG1 is needed for sterols to block Sar1-dependent Sec23/24 binding to SCAP. Reason: Exactly the mechanism: in vitro, sterol inhibition of COPII binding to SCAP depends on Insig-1. INSIG negatively regulates the loading of one specific cargo (SCAP-SREBP) into COPII vesicles. INSIG2 shows the same activity in a vesicle-budding assay (PMID:12242332), so the INSIG2 review adds this term as NEW. Supporting Evidence: PMID:15899885 This in vitro inhibition is dependent on the presence of Insig-1, an ER resident protein that is necessary for sterol-mediated inhibition of Scap/SREBP transport in intact cells. PMID:15899885 addition of cholesterol or 25-hydroxycholesterol to microsomal membranes in vitro blocks Sar1-dependent binding of the Sec23/24 complex to Scap, the SREBP escort protein PMID:17428919 Cholesterol and oxysterols block COPII binding to MELADL by binding to different intracellular receptors, cholesterol to Scap and oxysterols to Insig.

Gene Description

Existing Annotations Review

Core Functions

Sterol-dependent sequestration of SCAP: INSIG1 binds the sterol-sensing domain of sterol-loaded SCAP and keeps the SCAP-SREBP complex in the ER membrane by masking SCAP's COPII sorting signal, which blocks SREBP transport to the Golgi and its activation.

Oxysterol sensing: INSIG1 binds 25-hydroxycholesterol and related oxysterols, which drives its association with SCAP. The binding pocket is assigned to TM3/TM4 by homology with the SCAP-INSIG2 cryo-EM structure and by Insig TM3/TM4 mutants; no INSIG1 structure has been solved.

Substrate adaptor for sterol-accelerated ER-associated degradation: INSIG1 binds the sterol-sensing domain of HMG-CoA reductase and links it to ER ubiquitin ligases (gp78/AMFR, TRC8/RNF139, RNF145; also ACAT2 to gp78), lowering cholesterol synthesis.

References

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