{"gene":"INSIG1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2002,"finding":"INSIG-1 is an ER membrane protein that binds the sterol-sensing domain of SCAP in a sterol-dependent manner, as determined by coimmunoprecipitation and blue native-PAGE. This binding retains the SCAP/SREBP complex in the ER, preventing SREBP proteolytic processing in the Golgi. Mutant SCAP(Y298C) fails to bind INSIG-1 and is resistant to sterol-mediated ER retention.","method":"Coimmunoprecipitation, tandem mass spectrometry, blue native-PAGE, mutant SCAP(Y298C) functional analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP, mass spectrometry identification, blue native-PAGE, functional mutagenesis, replicated by multiple subsequent labs","pmids":["12202038"],"is_preprint":false},{"year":2003,"finding":"Sterol-induced binding of the sterol-sensing domain of HMG CoA reductase to insig-1 accelerates proteasomal degradation of reductase. Overexpression of the SCAP sterol-sensing domain inhibits this degradation, suggesting SCAP and reductase compete for the same binding site on insig-1. Insig-1 binding to reductase leads to ubiquitination and proteasome-dependent degradation, in contrast to its effect on SCAP (ER retention).","method":"Coimmunoprecipitation, proteasome inhibitor assays, competitive binding with SCAP sterol-sensing domain overexpression","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, pharmacological inhibition, competition assay, replicated by multiple subsequent studies","pmids":["12535518"],"is_preprint":false},{"year":2003,"finding":"Human INSIG-1 has a six-transmembrane topology with short N- and C-terminal cytosolic segments, five short luminal and cytosolic loops, and most of the protein buried within the membrane, as determined by protease protection, glycosylation site mapping, and cysteine derivatization.","method":"Protease protection assay, glycosylation site mapping, cysteine derivatization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — three orthogonal biochemical topology methods in a single study, single lab","pmids":["14660594"],"is_preprint":false},{"year":2004,"finding":"Insig-1 overexpression in transgenic mouse liver blocks SCAP-mediated escort of SREBPs to the Golgi, reducing nuclear SREBP levels (all isoforms), suppressing mRNAs for cholesterol/fatty acid/triglyceride synthesis enzymes, lowering plasma cholesterol, and blunting the insulin-stimulated rise in SREBP-1c upon refeeding.","method":"Transgenic mouse overexpression, nuclear SREBP quantification, lipid measurements, mRNA analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic overexpression with multiple orthogonal phenotypic readouts, replicated in two dietary conditions","pmids":["15085196"],"is_preprint":false},{"year":2004,"finding":"Hypotonic stress and ER stress (thapsigargin) activate SREBP proteolytic processing by reducing Insig-1 protein levels through inhibition of protein synthesis; Insig-2 is unaffected due to its slower turnover rate. Loss of Insig-1 (but not Insig-2) is sufficient to bypass sterol-mediated inhibition of SREBP processing.","method":"Hypotonic shock and thapsigargin treatment, protein synthesis inhibition, immunoblotting, SREBP processing assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function phenotype with defined molecular readout (SREBP processing), two orthogonal stress stimuli, single lab","pmids":["15304479"],"is_preprint":false},{"year":2005,"finding":"Gp78, a membrane-anchored ubiquitin E3 ligase, binds Insig-1 (with higher affinity than Insig-2) and is required for sterol-regulated ubiquitination of HMG CoA reductase. Gp78 also couples ubiquitination to degradation by binding VCP/p97 ATPase. Insig-1 thus serves as a bridge between gp78/VCP and the reductase substrate.","method":"Coimmunoprecipitation, siRNA knockdown of gp78, ubiquitination assays, reductase degradation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, loss-of-function (siRNA), functional ubiquitination assay, replicated by subsequent papers","pmids":["16168377"],"is_preprint":false},{"year":2005,"finding":"Genetic isolation of CHO cells (SRD-15) deficient in both Insig-1 and Insig-2 demonstrates an absolute requirement for Insig proteins: sterols neither inhibit SREBP processing nor promote reductase ubiquitination/degradation in these cells. Transfection with either Insig-1 or Insig-2 fully restores sterol regulation.","method":"Gamma-irradiation mutagenesis, 25-hydroxycholesterol selection, genetic complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — formal genetic loss-of-function (double KO cell line) with complementation rescue, two functional readouts","pmids":["15866869"],"is_preprint":false},{"year":2006,"finding":"Upon sterol deprivation, Insig-1 is ubiquitinated on lysines 156 and 158 and degraded by proteasomes. The Scap/SREBP complex dissociates from Insig-1 when sterols are depleted. Scap/SREBP binding to Insig-1 in sterol-replete conditions blocks its ubiquitination and stabilizes it. SREBP target genes include the Insig-1 gene itself, creating a feedback loop.","method":"Site-directed mutagenesis of Lys156/158, ubiquitination assays, proteasome inhibitor experiments, pulse-chase analysis","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis of specific ubiquitination sites, pharmacological inhibition, mechanistic dissection, replicated by subsequent work","pmids":["16399501"],"is_preprint":false},{"year":2006,"finding":"Gp78 is required for ubiquitination and degradation of Insig-1 in sterol-depleted cells. Sterols prevent Insig-1 ubiquitination by displacing gp78 from Insig-1, an event caused by sterol-induced binding of Scap to Insig-1. This explains why Scap is retained in the ER (rather than degraded) upon Insig-1 binding, while reductase is ubiquitinated and degraded.","method":"Coimmunoprecipitation, siRNA knockdown of gp78, sterol-regulated degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, siRNA loss-of-function, mechanistic displacement model tested, replicated by Tsai et al. 2012 with some discrepancy","pmids":["17043353"],"is_preprint":false},{"year":2006,"finding":"Conserved Asp-205 in Insig-1 (juxtamembranous to the fourth transmembrane helix, cytosolic face) is essential for both binding to Scap and binding to HMG CoA reductase. Ala substitution abolishes sterol-dependent Scap binding and SREBP cleavage inhibition, and also abolishes acceleration of reductase degradation. The equivalent Asp in Insig-2 is similarly required.","method":"Site-directed mutagenesis (Asp205Ala), coimmunoprecipitation, SREBP processing assay, reductase degradation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with two orthogonal functional readouts (SCAP binding / reductase degradation), single lab","pmids":["16606821"],"is_preprint":false},{"year":2008,"finding":"Unsaturated fatty acids stabilize Insig-1 without blocking its ubiquitination. Instead, they prevent extraction of ubiquitinated Insig-1 from ER membranes by blocking the interaction between Ubxd8 and Insig-1, thereby preventing VCP/p97 recruitment and membrane extraction. This post-ubiquitination step is distinct from the sterol-mediated pre-ubiquitination block.","method":"Ubiquitination assays, membrane extraction assays, coimmunoprecipitation of Ubxd8 and VCP with Insig-1, fatty acid treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, biochemical fractionation, mechanistic dissection of sequential ERAD steps, single lab with multiple orthogonal methods","pmids":["18835813"],"is_preprint":false},{"year":2009,"finding":"Insig-1 (and reductase) are dislocated to the cytosol as intact full-length polytopic proteins during ERAD, in a process requiring metabolic energy and the AAA-ATPase p97/VCP. Dislocation of reductase depends on Insig-1 and sterol-stimulated binding between them. Dislocation of Insig-1 itself is sterol-independent.","method":"Cytosolic fractionation, coimmunoprecipitation, p97/VCP functional inhibition, metabolic energy depletion","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation, Co-IP, pharmacological/energy-depletion experiments, single lab","pmids":["19458199"],"is_preprint":false},{"year":2009,"finding":"p97/VCP recruits proteasomes to Insig-1 (and to Insig-2(L210A) mutant) while the protein is still membrane-embedded, prior to extraction. A single amino acid difference (Leu-210 in Insig-2 vs. the corresponding residue in Insig-1) governs the rate of ubiquitination, sterol-regulated degradation, and pre-extraction proteasome recruitment.","method":"Site-directed mutagenesis (Insig-2 L210A), coimmunoprecipitation of proteasomes with membrane-embedded Insig, pulse-chase degradation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis identifying key residue, Co-IP of proteasomes with membrane substrate, mechanistic ordering of ERAD steps, single lab with multiple orthogonal methods","pmids":["19815544"],"is_preprint":false},{"year":2014,"finding":"Upon cytoplasmic DNA stimulation, the ER ubiquitin E3 ligase AMFR is recruited to STING in an INSIG1-dependent manner. The AMFR/INSIG1 complex catalyzes K27-linked polyubiquitination of STING, which serves as an anchoring platform for TBK1 recruitment and translocation to perinuclear microsomes. Depletion of INSIG1 impairs STING-mediated antiviral gene induction, and myeloid-cell-specific Insig1−/− mice are more susceptible to HSV-1 infection.","method":"Coimmunoprecipitation, siRNA/shRNA knockdown, Insig1 conditional knockout mice, antiviral gene induction assays, HSV-1 infection model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout with infection phenotype, ubiquitination site characterization, multiple orthogonal methods","pmids":["25526307"],"is_preprint":false},{"year":2018,"finding":"INSIG1 inhibits HIV-1 production by promoting degradation of the HIV-1 Gag protein. Unlike reductase degradation (which uses AMFR/gp78 and the proteasome), INSIG1 coordinates with the E3 ligase TRC8 to promote Gag degradation through the lysosome pathway at ER/endosomal membrane sites.","method":"Pseudovirus production assays, protein overexpression, gene knockouts, pathway inhibitor assays distinguishing proteasome vs. lysosome","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (knockouts), pathway pharmacology, functional viral assay, single lab","pmids":["30563842"],"is_preprint":false},{"year":2020,"finding":"AKT-phosphorylated PCK1 (at Ser90) translocates to the ER where it phosphorylates INSIG1 at Ser207 (and INSIG2 at Ser151). This phosphorylation reduces sterol binding to INSIG1/2, disrupts the INSIG-SCAP interaction, and causes SCAP-SREBP complex translocation to the Golgi, activating SREBP-driven lipogenesis in HCC cells.","method":"In vitro kinase assays, site-directed mutagenesis (Ser207 of INSIG1), coimmunoprecipitation, subcellular fractionation, mouse xenograft tumorigenesis models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution, active-site mutagenesis, Co-IP, in vivo mouse model, multiple orthogonal methods","pmids":["32322062"],"is_preprint":false},{"year":2021,"finding":"INSIG1 mediates oxysterol (25-hydroxycholesterol/27-hydroxycholesterol)-dependent activation of the PERK-eIF2α-ATF4 axis. Binding of oxysterols to INSIG is required; INSIG1/2-deficient CHO cells show attenuated ATF4 upregulation that is rescued by re-expression of either INSIG1 or INSIG2. ATF4 induction promotes cell death gene expression (Chop, Chac1, Trb3).","method":"INSIG1/2-deficient cell lines, rescue re-expression, PERK/eIF2α pathway inhibitors, siRNA knockdown of INSIG1 or INSIG2 in Huh7 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with rescue, pharmacological pathway dissection, single lab, two cell model systems","pmids":["34298014"],"is_preprint":false},{"year":2021,"finding":"Insig1 knockout mice with hyper-efficient SREBP activation, when challenged with a NASH-inducing diet, show remodeled hepatic lipidome and decreased hepatocellular damage despite enhanced lipid and cholesterol biosynthesis, indicating INSIG1/SCAP/SREBP governs transcriptional programs protecting the liver from lipotoxic insults.","method":"Insig1 knockout mouse model, NASH diet challenge, lipidomics, liver injury markers","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic KO with defined metabolic phenotype and lipidomics, single lab","pmids":["33722690"],"is_preprint":false},{"year":2025,"finding":"TRIM25 ubiquitinates and degrades INSIG1, thereby enhancing SREBP2 nuclear translocation and upregulating lipid biosynthesis genes; TRIM25 knockout mice show reduced INSIG1 ubiquitination and ameliorated MASH. A specific TRIM25 inhibitor decreases INSIG1 ubiquitination and attenuates hepatic lipid accumulation.","method":"TRIM25 knockout mice, Co-IP, ubiquitination assays, pharmacological TRIM25 inhibitor, MASH mouse model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockout and pharmacological inhibition, Co-IP ubiquitination assay, single lab","pmids":["40231613"],"is_preprint":false},{"year":2026,"finding":"ADSL translocates to the ER in a glucose/PKCε-dependent manner and promotes succination of INSIG1/2, disrupting INSIG-SCAP interaction and enabling SCAP-SREBP translocation to the Golgi and SREBP-1 activation for lipogenesis in hepatocellular carcinoma.","method":"Proximity ligation, Co-IP, mass spectrometry identification of succination sites, PKCε inhibition/activation, ADSL-ER translocation assays, mouse tumorigenesis model","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, PTM identification by MS, mouse in vivo model, single lab with multiple methods","pmids":["41833955"],"is_preprint":false},{"year":2026,"finding":"NFE2L1 binds INSIG1 via its N-terminal NHB2 domain; cholesterol enhances this interaction to drive INSIG1 degradation and SREBP1 activation, sustaining VLDL secretion. NFE2L1 deficiency elevates INSIG1 levels, suppresses SREBP1, and impairs VLDL secretion. The NHB2-deleted NFE2L1 mutant fails to restore SREBP1 activity or VLDL secretion.","method":"Coimmunoprecipitation, domain mutagenesis (ΔNHB2), NFE2L1-deficient mice, lipidomics, VLDL secretion assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutagenesis, in vivo mouse KO, lipidomics; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.06.09.657856"],"is_preprint":true},{"year":2026,"finding":"Insig1 interacts with death-associated protein kinase 3 (Dapk3) and stabilizes Dapk3 protein levels. Conditional knockout of Insig1 in renal tubular epithelial cells markedly reduces cisplatin- or ischemia-reperfusion-induced kidney injury. Pharmacological inhibition of Dapk3 recapitulates the renoprotective effect of Insig1 ablation.","method":"Proteomics identification of Insig1-interacting proteins, conditional tubular Insig1 KO mice (cisplatin and I/R AKI models), siRNA knockdown, Dapk3 inhibitor (HS148)","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics-identified interaction, in vivo conditional KO, pharmacological validation, single lab","pmids":["42144057"],"is_preprint":false},{"year":2012,"finding":"gp78 is required for sterol-regulated degradation of Insig-1 (but not for the robust sterol-accelerated degradation of HMG-CoA reductase), as shown in gp78-knockout mouse embryonic fibroblasts, contradicting the previously reported role of gp78 in reductase ERAD.","method":"gp78 knockout mouse embryonic fibroblasts, RNAi in fibroblast cell lines, reductase and Insig-1 degradation assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout MEFs with two orthogonal approaches (KO + RNAi), single lab; partially contradicts prior work on reductase","pmids":["23087214"],"is_preprint":false},{"year":2013,"finding":"Lipid-regulated ERAD of mammalian Insig-1 was reconstituted in Drosophila S2 cells. Insig-1 degradation is inhibited by either sterols (blocking ubiquitination) or unsaturated fatty acids (blocking membrane extraction), and genetic/pharmacologic manipulations demonstrate that Insig-1 and reductase are degraded through distinct mechanisms mediated by different ubiquitin ligase complexes.","method":"Reconstitution of mammalian Insig-1 ERAD in Drosophila S2 cells, genetic manipulations, pharmacological inhibitors, subcellular fractionation","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in heterologous cell system, genetic and pharmacological dissection, multiple orthogonal methods, single lab","pmids":["23403031"],"is_preprint":false}],"current_model":"INSIG1 is an ER-resident six-transmembrane protein that acts as a central sterol sensor and scaffolding hub: upon sterol accumulation it binds the sterol-sensing domains of both SCAP (retaining the SCAP/SREBP complex in the ER and blocking SREBP proteolytic activation) and HMG CoA reductase (recruiting the E3 ligase gp78 and VCP/p97 to drive ubiquitin-proteasomal reductase degradation via ERAD); in sterol-depleted cells INSIG1 itself is ubiquitinated at Lys-156/158 by gp78 and degraded, while unsaturated fatty acids stabilize it post-ubiquitination by blocking Ubxd8-mediated VCP recruitment; additionally, phosphorylation by PCK1 (Ser207) or succination by ADSL disrupts INSIG1-SCAP binding to activate lipogenic SREBPs in cancer; and beyond lipid homeostasis, INSIG1 mediates oxysterol-triggered PERK-eIF2α-ATF4 ER stress signaling, supports STING K27-ubiquitination and TBK1 recruitment for antiviral innate immunity (with the E3 ligase AMFR), and interacts with Dapk3 to promote tubular cell apoptosis in kidney injury."},"narrative":{"mechanistic_narrative":"INSIG1 is an ER-resident polytopic membrane protein that serves as the central sterol sensor governing cellular lipid homeostasis through the SCAP/SREBP and HMG CoA reductase axes [PMID:12202038, PMID:15866869]. It adopts a six-transmembrane topology with cytosolic N- and C-termini, most of the protein buried within the membrane [PMID:14660594], and a conserved cytosolic-facing Asp-205 that is essential for both of its key binding activities [PMID:16606821]. In sterol-replete cells INSIG1 binds the sterol-sensing domain of SCAP, retaining the SCAP/SREBP complex in the ER and blocking SREBP transport to the Golgi for proteolytic activation; the SCAP(Y298C) mutant escapes this retention [PMID:12202038], and INSIG1 overexpression in vivo suppresses nuclear SREBP and the full lipogenic transcriptional program [PMID:15085196]. The same Asp-205-dependent surface binds the sterol-sensing domain of HMG CoA reductase, but with the opposite outcome: INSIG1 bridges the reductase to the membrane E3 ligase gp78 and the AAA-ATPase VCP/p97 to drive its ubiquitin-proteasomal ERAD [PMID:12535518, PMID:16168377, PMID:16606821]. The divergent fates of the two partners — ER retention of SCAP versus degradation of reductase — arise because sterol-induced SCAP binding displaces gp78 from INSIG1, protecting it from ubiquitination [PMID:17043353]. In sterol-depleted cells INSIG1 itself is ubiquitinated on Lys-156/158 and degraded, completing a feedback loop in which the INSIG1 gene is an SREBP target [PMID:16399501]; unsaturated fatty acids stabilize ubiquitinated INSIG1 by blocking Ubxd8-mediated VCP recruitment and membrane extraction, a step distinct from the sterol block on ubiquitination [PMID:18835813, PMID:23403031]. INSIG1 abundance is thus a rheostat: its loss under hypotonic or ER stress bypasses sterol inhibition of SREBP processing [PMID:15304479], and oncogenic signals override it — PCK1 phosphorylates INSIG1 at Ser207 and ADSL succinates it, both disrupting the INSIG-SCAP interaction to activate lipogenic SREBPs in hepatocellular carcinoma [PMID:32322062, PMID:41833955], while TRIM25 ubiquitinates INSIG1 to enhance SREBP nuclear translocation in metabolic liver disease [PMID:40231613]. Beyond lipid control, INSIG1 functions as a scaffold in innate immunity, recruiting the E3 ligase AMFR to STING to catalyze K27-linked polyubiquitination and TBK1 recruitment for antiviral signaling [PMID:25526307], and it mediates oxysterol-triggered PERK-eIF2α-ATF4 ER stress and cell-death signaling [PMID:34298014].","teleology":[{"year":2002,"claim":"Established INSIG1 as the missing sterol-dependent retention factor that explains how high sterols keep SREBP inactive, by identifying its sterol-regulated binding to the SCAP sterol-sensing domain.","evidence":"Co-IP, mass spectrometry, blue native-PAGE, and SCAP(Y298C) functional mutant in cultured cells","pmids":["12202038"],"confidence":"High","gaps":["Did not resolve how the same protein could produce opposite fates for different sterol-sensing-domain partners","No structural model of the sterol-INSIG1 interface"]},{"year":2003,"claim":"Revealed the second arm of INSIG1 function — sterol-dependent binding to HMG CoA reductase that triggers its proteasomal degradation — and showed SCAP and reductase compete for the same INSIG1 site, defining a shared regulatory hub.","evidence":"Co-IP, proteasome inhibitor assays, and competition with overexpressed SCAP sterol-sensing domain","pmids":["12535518"],"confidence":"High","gaps":["Identity of the E3 ligase and dislocation machinery not yet known","Mechanism dictating retention vs. degradation unexplained"]},{"year":2003,"claim":"Defined the membrane architecture of INSIG1 as a six-transmembrane protein with cytosolic termini, providing the topological framework for interpreting its binding and PTM sites.","evidence":"Protease protection, glycosylation site mapping, and cysteine derivatization","pmids":["14660594"],"confidence":"High","gaps":["No high-resolution structure","Location of the sterol-binding pocket not mapped"]},{"year":2004,"claim":"Demonstrated in vivo that INSIG1 dosage controls the entire lipogenic transcriptional program, and that its abundance is acutely regulated — stress-induced loss of INSIG1 alone bypasses sterol inhibition of SREBP.","evidence":"Transgenic mouse liver overexpression with lipid/mRNA readouts, and hypotonic/thapsigargin stress with protein-synthesis inhibition in cells","pmids":["15085196","15304479"],"confidence":"Medium","gaps":["Mechanism of INSIG1 turnover and degradation not yet defined","Why Insig-2 is spared was attributed to turnover rate without molecular detail"]},{"year":2005,"claim":"Identified gp78 and VCP/p97 as the ubiquitination-extraction machinery INSIG1 recruits, and proved via double-knockout cells that INSIG proteins are absolutely required for all sterol regulation of SREBP and reductase.","evidence":"Co-IP and siRNA of gp78 with ubiquitination assays; SRD-15 Insig1/2-double-deficient CHO cells with complementation rescue","pmids":["16168377","15866869"],"confidence":"High","gaps":["Insig-1 vs Insig-2 functional redundancy not separated in vivo","Did not address INSIG1's own degradation"]},{"year":2006,"claim":"Resolved the central paradox of INSIG1 dual function: sterol depletion triggers gp78-mediated ubiquitination of INSIG1 at Lys-156/158 and its degradation, while sterol-induced SCAP binding displaces gp78 to stabilize INSIG1, and the conserved Asp-205 is required for both SCAP and reductase binding.","evidence":"Lys156/158 and Asp205Ala mutagenesis, ubiquitination and pulse-chase assays, gp78 siRNA, and SREBP/reductase functional readouts","pmids":["16399501","17043353","16606821"],"confidence":"High","gaps":["Atomic basis for sterol-induced gp78 displacement not resolved","Whether the feedback loop fully accounts for INSIG1 oscillation in vivo untested"]},{"year":2008,"claim":"Uncovered a second, lipid-class-specific layer of INSIG1 regulation — unsaturated fatty acids stabilize ubiquitinated INSIG1 by blocking Ubxd8-dependent VCP recruitment and membrane extraction, separating ubiquitination from dislocation.","evidence":"Ubiquitination and membrane extraction assays with Ubxd8/VCP Co-IP under fatty acid treatment","pmids":["18835813"],"confidence":"High","gaps":["How fatty acid signal is sensed at the membrane unclear","Physiological context of this stabilization in vivo not established here"]},{"year":2009,"claim":"Ordered the ERAD steps mechanistically, showing INSIG1 is dislocated to the cytosol as an intact polytopic protein, that p97/VCP recruits proteasomes to membrane-embedded INSIG1 prior to extraction, and that a single residue (Leu-210 in Insig-2) sets the degradation rate.","evidence":"Cytosolic fractionation, p97/VCP inhibition, energy depletion, Insig-2 L210A mutagenesis, and proteasome Co-IP with membrane substrate","pmids":["19458199","19815544"],"confidence":"Medium","gaps":["Structural mechanism of polytopic dislocation unknown","Single-lab evidence for pre-extraction proteasome recruitment"]},{"year":2013,"claim":"Reconstituted lipid-regulated INSIG1 ERAD in a heterologous Drosophila system, confirming that sterols and unsaturated fatty acids inhibit degradation at distinct steps and that INSIG1 and reductase use different ligase complexes.","evidence":"Reconstitution in Drosophila S2 cells with genetic and pharmacological dissection plus fractionation","pmids":["23403031"],"confidence":"High","gaps":["Exact ligase complement in mammalian cells partly contested (see gp78 reassessment)"]},{"year":2012,"claim":"Reassessed the E3 ligase requirement using gp78-knockout MEFs, finding gp78 needed for INSIG1 degradation but not for robust sterol-accelerated reductase degradation, contradicting the earlier reductase model.","evidence":"gp78 knockout MEFs and RNAi with INSIG1 and reductase degradation assays","pmids":["23087214"],"confidence":"Medium","gaps":["Source of discrepancy with prior gp78/reductase work unresolved","Alternative reductase ligase not identified here"]},{"year":2014,"claim":"Extended INSIG1 beyond lipid metabolism by showing it is required to recruit the E3 ligase AMFR to STING for K27-linked ubiquitination and TBK1-dependent antiviral signaling.","evidence":"Co-IP, knockdown, myeloid-specific Insig1 KO mice, and HSV-1 infection model","pmids":["25526307"],"confidence":"High","gaps":["How INSIG1 toggles between lipid and immune scaffolding roles unknown","Whether sterol status modulates the STING function untested"]},{"year":2018,"claim":"Identified an additional antiviral role in which INSIG1 partners with TRC8 to route HIV-1 Gag to lysosomal degradation, distinct from the proteasomal reductase pathway.","evidence":"Pseudovirus assays, knockouts, and proteasome-vs-lysosome inhibitor pharmacology","pmids":["30563842"],"confidence":"Medium","gaps":["Direct INSIG1-Gag interaction not biochemically resolved","Single-lab finding"]},{"year":2021,"claim":"Linked INSIG1 to ER stress and protective metabolic programs, showing it mediates oxysterol-dependent PERK-eIF2α-ATF4 activation and that Insig1 loss in vivo remodels the hepatic lipidome to reduce lipotoxic liver damage.","evidence":"INSIG1/2-deficient cells with rescue and PERK pathway inhibitors; Insig1 KO mice on NASH diet with lipidomics","pmids":["34298014","33722690"],"confidence":"Medium","gaps":["Direct oxysterol-INSIG1 sensing in PERK activation not structurally defined","Mechanism connecting SREBP hyperactivation to hepatoprotection incomplete"]},{"year":2020,"claim":"Established that oncogenic signaling overrides INSIG1 sterol gating: PCK1 phosphorylates INSIG1 at Ser207 to reduce sterol binding and release SCAP-SREBP for lipogenesis in HCC.","evidence":"In vitro kinase assays, Ser207 mutagenesis, Co-IP, fractionation, and xenograft tumorigenesis","pmids":["32322062"],"confidence":"High","gaps":["Whether phosphorylation also alters INSIG1 degradation kinetics not addressed"]},{"year":2026,"claim":"Expanded the post-translational control of INSIG1 in disease, showing TRIM25-mediated ubiquitination, ADSL-mediated succination, and cholesterol-enhanced NFE2L1 binding each disrupt INSIG1 to activate SREBP-driven lipogenesis or VLDL secretion.","evidence":"Co-IP, PTM mapping, domain mutagenesis, knockout mice, and pharmacological inhibitors across MASH/HCC/VLDL models","pmids":["40231613","41833955","bio_10.1101_2025.06.09.657856"],"confidence":"Medium","gaps":["Hierarchy and crosstalk among these competing PTM/binding events unknown","NFE2L1 finding is a preprint"]},{"year":2026,"claim":"Revealed a metabolism-independent role in which INSIG1 binds and stabilizes Dapk3 to promote tubular cell death in acute kidney injury.","evidence":"Proteomics interaction screen, conditional tubular Insig1 KO mice in cisplatin and I/R AKI, and Dapk3 inhibitor","pmids":["42144057"],"confidence":"Medium","gaps":["Direct INSIG1-Dapk3 binding interface not mapped","Whether sterol sensing contributes is unaddressed"]},{"year":null,"claim":"How INSIG1 partitions among its competing roles — sterol gating of SCAP, reductase ERAD targeting, immune and apoptotic scaffolding — and how its many PTMs are hierarchically integrated remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of INSIG1 with sterol or partners","No unified model coordinating phosphorylation, succination, and ubiquitination","Tissue-specific selection among lipid vs. non-lipid functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,1,16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,13]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,7]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,5]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5,7,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[16]}],"complexes":["SCAP/SREBP-INSIG1 complex","INSIG1-gp78-VCP ERAD complex","AMFR/INSIG1-STING complex"],"partners":["SCAP","HMGCR","AMFR","VCP","FAF2","STING1","PCK1","DAPK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15503","full_name":"Insulin-induced gene 1 protein","aliases":[],"length_aa":277,"mass_kda":30.0,"function":"Oxysterol-binding protein that mediates feedback control of cholesterol synthesis by controlling both endoplasmic reticulum to Golgi transport of SCAP and degradation of HMGCR (PubMed:12202038, PubMed:12535518, PubMed:16168377, PubMed:16399501, PubMed:16606821, PubMed:32322062). Acts as a negative regulator of cholesterol biosynthesis by mediating the retention of the SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the processing of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:12202038, PubMed:16399501, PubMed:26311497, PubMed:32322062). Binds oxysterol, including 25-hydroxycholesterol, regulating interaction with SCAP and retention of the SCAP-SREBP complex in the endoplasmic reticulum (PubMed:32322062). In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP complex in the endoplasmic reticulum, thereby preventing SCAP from escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi (PubMed:15899885, PubMed:32322062). Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding, disrupting the interaction between INSIG1 and SCAP, thereby promoting Golgi transport of the SCAP-SREBP complex, followed by processing and nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (PubMed:26311497, PubMed:32322062). Also regulates cholesterol synthesis by regulating degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated degradation (ERAD) of HMGCR via recruitment of the reductase to the ubiquitin ligases AMFR/gp78 and/or RNF139 (PubMed:12535518, PubMed:16168377, PubMed:22143767). Also regulates degradation of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78 (PubMed:28604676)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O15503/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INSIG1","classification":"Not Classified","n_dependent_lines":10,"n_total_lines":1208,"dependency_fraction":0.008278145695364239},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INSIG1","total_profiled":1310},"omim":[{"mim_id":"620640","title":"RING FINGER PROTEIN 145; RNF145","url":"https://www.omim.org/entry/620640"},{"mim_id":"614168","title":"PHOSPHOENOLPYRUVATE CARBOXYKINASE 1, SOLUBLE; PCK1","url":"https://www.omim.org/entry/614168"},{"mim_id":"608660","title":"INSULIN-INDUCED GENE 2; INSIG2","url":"https://www.omim.org/entry/608660"},{"mim_id":"603243","title":"AUTOCRINE MOTILITY FACTOR RECEPTOR; AMFR","url":"https://www.omim.org/entry/603243"},{"mim_id":"602055","title":"INSULIN-INDUCED GENE 1; INSIG1","url":"https://www.omim.org/entry/602055"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":526.8}],"url":"https://www.proteinatlas.org/search/INSIG1"},"hgnc":{"alias_symbol":["CL-6","MGC1405"],"prev_symbol":[]},"alphafold":{"accession":"O15503","domains":[{"cath_id":"1.10.3760","chopping":"82-270","consensus_level":"medium","plddt":78.805,"start":82,"end":270}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15503","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15503-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15503-F1-predicted_aligned_error_v6.png","plddt_mean":68.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INSIG1","jax_strain_url":"https://www.jax.org/strain/search?query=INSIG1"},"sequence":{"accession":"O15503","fasta_url":"https://rest.uniprot.org/uniprotkb/O15503.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15503/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15503"}},"corpus_meta":[{"pmid":"12202038","id":"PMC_12202038","title":"Crucial 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Yi xue ban = Journal of Central South University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18382059","citation_count":2,"is_preprint":false},{"pmid":"41526656","id":"PMC_41526656","title":"INSIG1 parallel substitution drives lipid/sterol metabolic plasticity mediating desert adaptation in ungulates.","date":"2026","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41526656","citation_count":1,"is_preprint":false},{"pmid":"29356579","id":"PMC_29356579","title":"Insulin Treatment Cannot Promote Lipogenesis in Rat Fetal Lung in Gestational Diabetes Mellitus Because of Failure to Redress the Imbalance Among SREBP-1, SCAP, and INSIG-1.","date":"2018","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29356579","citation_count":1,"is_preprint":false},{"pmid":"41833955","id":"PMC_41833955","title":"INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41833955","citation_count":0,"is_preprint":false},{"pmid":"38828915","id":"PMC_38828915","title":"Circular RNA_015343 sponges microRNA-25 to regulate viability, proliferation, and milk fat synthesis of ovine mammary epithelial cells via INSIG1.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38828915","citation_count":0,"is_preprint":false},{"pmid":"42144057","id":"PMC_42144057","title":"Insig1 deficiency protects against acute kidney injury via targeting Dapk3.","date":"2026","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/42144057","citation_count":0,"is_preprint":false},{"pmid":"42043177","id":"PMC_42043177","title":"Mixed Heavy Metal Exposure During Pregnancy Induces GDM-like Metabolic Dysfunction Associated with Glycer-Ophospholipid Metabolic Reprogramming and Altered Insig1 Expression: A Multi-Omics Study in Rats.","date":"2026","source":"Toxics","url":"https://pubmed.ncbi.nlm.nih.gov/42043177","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.09.657856","title":"Cholesterol-Responsive Interaction of NFE2L1-INSIG1 Controls VLDL Secretion and MASH Pathogenesis","date":"2025-06-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.09.657856","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.08.647685","title":"Hepatic isomiR landscaping reveals new biological insights into metabolic dysfunction in steatotic liver disease","date":"2025-04-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.08.647685","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.28.667272","title":"Dynamic Regulation of Cholesterol Metabolism Genes in Dopaminergic Neurons following Methamphetamine Treatment as Revealed by Single-Nucleus RNA Sequencing","date":"2025-07-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.28.667272","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.30.662298","title":"Nuclear Myosin 1 links genomic architecture to adipose tissue remodeling, metabolic inflammation and obesity in mice","date":"2025-07-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.30.662298","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":36004,"output_tokens":6421,"usd":0.102164,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15198,"output_tokens":5666,"usd":0.10882,"stage2_stop_reason":"end_turn"},"total_usd":0.210984,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"INSIG-1 is an ER membrane protein that binds the sterol-sensing domain of SCAP in a sterol-dependent manner, as determined by coimmunoprecipitation and blue native-PAGE. This binding retains the SCAP/SREBP complex in the ER, preventing SREBP proteolytic processing in the Golgi. Mutant SCAP(Y298C) fails to bind INSIG-1 and is resistant to sterol-mediated ER retention.\",\n      \"method\": \"Coimmunoprecipitation, tandem mass spectrometry, blue native-PAGE, mutant SCAP(Y298C) functional analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP, mass spectrometry identification, blue native-PAGE, functional mutagenesis, replicated by multiple subsequent labs\",\n      \"pmids\": [\"12202038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Sterol-induced binding of the sterol-sensing domain of HMG CoA reductase to insig-1 accelerates proteasomal degradation of reductase. Overexpression of the SCAP sterol-sensing domain inhibits this degradation, suggesting SCAP and reductase compete for the same binding site on insig-1. Insig-1 binding to reductase leads to ubiquitination and proteasome-dependent degradation, in contrast to its effect on SCAP (ER retention).\",\n      \"method\": \"Coimmunoprecipitation, proteasome inhibitor assays, competitive binding with SCAP sterol-sensing domain overexpression\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, pharmacological inhibition, competition assay, replicated by multiple subsequent studies\",\n      \"pmids\": [\"12535518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human INSIG-1 has a six-transmembrane topology with short N- and C-terminal cytosolic segments, five short luminal and cytosolic loops, and most of the protein buried within the membrane, as determined by protease protection, glycosylation site mapping, and cysteine derivatization.\",\n      \"method\": \"Protease protection assay, glycosylation site mapping, cysteine derivatization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — three orthogonal biochemical topology methods in a single study, single lab\",\n      \"pmids\": [\"14660594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Insig-1 overexpression in transgenic mouse liver blocks SCAP-mediated escort of SREBPs to the Golgi, reducing nuclear SREBP levels (all isoforms), suppressing mRNAs for cholesterol/fatty acid/triglyceride synthesis enzymes, lowering plasma cholesterol, and blunting the insulin-stimulated rise in SREBP-1c upon refeeding.\",\n      \"method\": \"Transgenic mouse overexpression, nuclear SREBP quantification, lipid measurements, mRNA analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic overexpression with multiple orthogonal phenotypic readouts, replicated in two dietary conditions\",\n      \"pmids\": [\"15085196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Hypotonic stress and ER stress (thapsigargin) activate SREBP proteolytic processing by reducing Insig-1 protein levels through inhibition of protein synthesis; Insig-2 is unaffected due to its slower turnover rate. Loss of Insig-1 (but not Insig-2) is sufficient to bypass sterol-mediated inhibition of SREBP processing.\",\n      \"method\": \"Hypotonic shock and thapsigargin treatment, protein synthesis inhibition, immunoblotting, SREBP processing assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function phenotype with defined molecular readout (SREBP processing), two orthogonal stress stimuli, single lab\",\n      \"pmids\": [\"15304479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Gp78, a membrane-anchored ubiquitin E3 ligase, binds Insig-1 (with higher affinity than Insig-2) and is required for sterol-regulated ubiquitination of HMG CoA reductase. Gp78 also couples ubiquitination to degradation by binding VCP/p97 ATPase. Insig-1 thus serves as a bridge between gp78/VCP and the reductase substrate.\",\n      \"method\": \"Coimmunoprecipitation, siRNA knockdown of gp78, ubiquitination assays, reductase degradation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, loss-of-function (siRNA), functional ubiquitination assay, replicated by subsequent papers\",\n      \"pmids\": [\"16168377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Genetic isolation of CHO cells (SRD-15) deficient in both Insig-1 and Insig-2 demonstrates an absolute requirement for Insig proteins: sterols neither inhibit SREBP processing nor promote reductase ubiquitination/degradation in these cells. Transfection with either Insig-1 or Insig-2 fully restores sterol regulation.\",\n      \"method\": \"Gamma-irradiation mutagenesis, 25-hydroxycholesterol selection, genetic complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — formal genetic loss-of-function (double KO cell line) with complementation rescue, two functional readouts\",\n      \"pmids\": [\"15866869\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Upon sterol deprivation, Insig-1 is ubiquitinated on lysines 156 and 158 and degraded by proteasomes. The Scap/SREBP complex dissociates from Insig-1 when sterols are depleted. Scap/SREBP binding to Insig-1 in sterol-replete conditions blocks its ubiquitination and stabilizes it. SREBP target genes include the Insig-1 gene itself, creating a feedback loop.\",\n      \"method\": \"Site-directed mutagenesis of Lys156/158, ubiquitination assays, proteasome inhibitor experiments, pulse-chase analysis\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis of specific ubiquitination sites, pharmacological inhibition, mechanistic dissection, replicated by subsequent work\",\n      \"pmids\": [\"16399501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Gp78 is required for ubiquitination and degradation of Insig-1 in sterol-depleted cells. Sterols prevent Insig-1 ubiquitination by displacing gp78 from Insig-1, an event caused by sterol-induced binding of Scap to Insig-1. This explains why Scap is retained in the ER (rather than degraded) upon Insig-1 binding, while reductase is ubiquitinated and degraded.\",\n      \"method\": \"Coimmunoprecipitation, siRNA knockdown of gp78, sterol-regulated degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, siRNA loss-of-function, mechanistic displacement model tested, replicated by Tsai et al. 2012 with some discrepancy\",\n      \"pmids\": [\"17043353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Conserved Asp-205 in Insig-1 (juxtamembranous to the fourth transmembrane helix, cytosolic face) is essential for both binding to Scap and binding to HMG CoA reductase. Ala substitution abolishes sterol-dependent Scap binding and SREBP cleavage inhibition, and also abolishes acceleration of reductase degradation. The equivalent Asp in Insig-2 is similarly required.\",\n      \"method\": \"Site-directed mutagenesis (Asp205Ala), coimmunoprecipitation, SREBP processing assay, reductase degradation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with two orthogonal functional readouts (SCAP binding / reductase degradation), single lab\",\n      \"pmids\": [\"16606821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Unsaturated fatty acids stabilize Insig-1 without blocking its ubiquitination. Instead, they prevent extraction of ubiquitinated Insig-1 from ER membranes by blocking the interaction between Ubxd8 and Insig-1, thereby preventing VCP/p97 recruitment and membrane extraction. This post-ubiquitination step is distinct from the sterol-mediated pre-ubiquitination block.\",\n      \"method\": \"Ubiquitination assays, membrane extraction assays, coimmunoprecipitation of Ubxd8 and VCP with Insig-1, fatty acid treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, biochemical fractionation, mechanistic dissection of sequential ERAD steps, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18835813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Insig-1 (and reductase) are dislocated to the cytosol as intact full-length polytopic proteins during ERAD, in a process requiring metabolic energy and the AAA-ATPase p97/VCP. Dislocation of reductase depends on Insig-1 and sterol-stimulated binding between them. Dislocation of Insig-1 itself is sterol-independent.\",\n      \"method\": \"Cytosolic fractionation, coimmunoprecipitation, p97/VCP functional inhibition, metabolic energy depletion\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation, Co-IP, pharmacological/energy-depletion experiments, single lab\",\n      \"pmids\": [\"19458199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"p97/VCP recruits proteasomes to Insig-1 (and to Insig-2(L210A) mutant) while the protein is still membrane-embedded, prior to extraction. A single amino acid difference (Leu-210 in Insig-2 vs. the corresponding residue in Insig-1) governs the rate of ubiquitination, sterol-regulated degradation, and pre-extraction proteasome recruitment.\",\n      \"method\": \"Site-directed mutagenesis (Insig-2 L210A), coimmunoprecipitation of proteasomes with membrane-embedded Insig, pulse-chase degradation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis identifying key residue, Co-IP of proteasomes with membrane substrate, mechanistic ordering of ERAD steps, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19815544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Upon cytoplasmic DNA stimulation, the ER ubiquitin E3 ligase AMFR is recruited to STING in an INSIG1-dependent manner. The AMFR/INSIG1 complex catalyzes K27-linked polyubiquitination of STING, which serves as an anchoring platform for TBK1 recruitment and translocation to perinuclear microsomes. Depletion of INSIG1 impairs STING-mediated antiviral gene induction, and myeloid-cell-specific Insig1−/− mice are more susceptible to HSV-1 infection.\",\n      \"method\": \"Coimmunoprecipitation, siRNA/shRNA knockdown, Insig1 conditional knockout mice, antiviral gene induction assays, HSV-1 infection model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vivo knockout with infection phenotype, ubiquitination site characterization, multiple orthogonal methods\",\n      \"pmids\": [\"25526307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"INSIG1 inhibits HIV-1 production by promoting degradation of the HIV-1 Gag protein. Unlike reductase degradation (which uses AMFR/gp78 and the proteasome), INSIG1 coordinates with the E3 ligase TRC8 to promote Gag degradation through the lysosome pathway at ER/endosomal membrane sites.\",\n      \"method\": \"Pseudovirus production assays, protein overexpression, gene knockouts, pathway inhibitor assays distinguishing proteasome vs. lysosome\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (knockouts), pathway pharmacology, functional viral assay, single lab\",\n      \"pmids\": [\"30563842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKT-phosphorylated PCK1 (at Ser90) translocates to the ER where it phosphorylates INSIG1 at Ser207 (and INSIG2 at Ser151). This phosphorylation reduces sterol binding to INSIG1/2, disrupts the INSIG-SCAP interaction, and causes SCAP-SREBP complex translocation to the Golgi, activating SREBP-driven lipogenesis in HCC cells.\",\n      \"method\": \"In vitro kinase assays, site-directed mutagenesis (Ser207 of INSIG1), coimmunoprecipitation, subcellular fractionation, mouse xenograft tumorigenesis models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution, active-site mutagenesis, Co-IP, in vivo mouse model, multiple orthogonal methods\",\n      \"pmids\": [\"32322062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"INSIG1 mediates oxysterol (25-hydroxycholesterol/27-hydroxycholesterol)-dependent activation of the PERK-eIF2α-ATF4 axis. Binding of oxysterols to INSIG is required; INSIG1/2-deficient CHO cells show attenuated ATF4 upregulation that is rescued by re-expression of either INSIG1 or INSIG2. ATF4 induction promotes cell death gene expression (Chop, Chac1, Trb3).\",\n      \"method\": \"INSIG1/2-deficient cell lines, rescue re-expression, PERK/eIF2α pathway inhibitors, siRNA knockdown of INSIG1 or INSIG2 in Huh7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with rescue, pharmacological pathway dissection, single lab, two cell model systems\",\n      \"pmids\": [\"34298014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Insig1 knockout mice with hyper-efficient SREBP activation, when challenged with a NASH-inducing diet, show remodeled hepatic lipidome and decreased hepatocellular damage despite enhanced lipid and cholesterol biosynthesis, indicating INSIG1/SCAP/SREBP governs transcriptional programs protecting the liver from lipotoxic insults.\",\n      \"method\": \"Insig1 knockout mouse model, NASH diet challenge, lipidomics, liver injury markers\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic KO with defined metabolic phenotype and lipidomics, single lab\",\n      \"pmids\": [\"33722690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM25 ubiquitinates and degrades INSIG1, thereby enhancing SREBP2 nuclear translocation and upregulating lipid biosynthesis genes; TRIM25 knockout mice show reduced INSIG1 ubiquitination and ameliorated MASH. A specific TRIM25 inhibitor decreases INSIG1 ubiquitination and attenuates hepatic lipid accumulation.\",\n      \"method\": \"TRIM25 knockout mice, Co-IP, ubiquitination assays, pharmacological TRIM25 inhibitor, MASH mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockout and pharmacological inhibition, Co-IP ubiquitination assay, single lab\",\n      \"pmids\": [\"40231613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ADSL translocates to the ER in a glucose/PKCε-dependent manner and promotes succination of INSIG1/2, disrupting INSIG-SCAP interaction and enabling SCAP-SREBP translocation to the Golgi and SREBP-1 activation for lipogenesis in hepatocellular carcinoma.\",\n      \"method\": \"Proximity ligation, Co-IP, mass spectrometry identification of succination sites, PKCε inhibition/activation, ADSL-ER translocation assays, mouse tumorigenesis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, PTM identification by MS, mouse in vivo model, single lab with multiple methods\",\n      \"pmids\": [\"41833955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NFE2L1 binds INSIG1 via its N-terminal NHB2 domain; cholesterol enhances this interaction to drive INSIG1 degradation and SREBP1 activation, sustaining VLDL secretion. NFE2L1 deficiency elevates INSIG1 levels, suppresses SREBP1, and impairs VLDL secretion. The NHB2-deleted NFE2L1 mutant fails to restore SREBP1 activity or VLDL secretion.\",\n      \"method\": \"Coimmunoprecipitation, domain mutagenesis (ΔNHB2), NFE2L1-deficient mice, lipidomics, VLDL secretion assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutagenesis, in vivo mouse KO, lipidomics; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.09.657856\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Insig1 interacts with death-associated protein kinase 3 (Dapk3) and stabilizes Dapk3 protein levels. Conditional knockout of Insig1 in renal tubular epithelial cells markedly reduces cisplatin- or ischemia-reperfusion-induced kidney injury. Pharmacological inhibition of Dapk3 recapitulates the renoprotective effect of Insig1 ablation.\",\n      \"method\": \"Proteomics identification of Insig1-interacting proteins, conditional tubular Insig1 KO mice (cisplatin and I/R AKI models), siRNA knockdown, Dapk3 inhibitor (HS148)\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics-identified interaction, in vivo conditional KO, pharmacological validation, single lab\",\n      \"pmids\": [\"42144057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"gp78 is required for sterol-regulated degradation of Insig-1 (but not for the robust sterol-accelerated degradation of HMG-CoA reductase), as shown in gp78-knockout mouse embryonic fibroblasts, contradicting the previously reported role of gp78 in reductase ERAD.\",\n      \"method\": \"gp78 knockout mouse embryonic fibroblasts, RNAi in fibroblast cell lines, reductase and Insig-1 degradation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout MEFs with two orthogonal approaches (KO + RNAi), single lab; partially contradicts prior work on reductase\",\n      \"pmids\": [\"23087214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lipid-regulated ERAD of mammalian Insig-1 was reconstituted in Drosophila S2 cells. Insig-1 degradation is inhibited by either sterols (blocking ubiquitination) or unsaturated fatty acids (blocking membrane extraction), and genetic/pharmacologic manipulations demonstrate that Insig-1 and reductase are degraded through distinct mechanisms mediated by different ubiquitin ligase complexes.\",\n      \"method\": \"Reconstitution of mammalian Insig-1 ERAD in Drosophila S2 cells, genetic manipulations, pharmacological inhibitors, subcellular fractionation\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in heterologous cell system, genetic and pharmacological dissection, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"23403031\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INSIG1 is an ER-resident six-transmembrane protein that acts as a central sterol sensor and scaffolding hub: upon sterol accumulation it binds the sterol-sensing domains of both SCAP (retaining the SCAP/SREBP complex in the ER and blocking SREBP proteolytic activation) and HMG CoA reductase (recruiting the E3 ligase gp78 and VCP/p97 to drive ubiquitin-proteasomal reductase degradation via ERAD); in sterol-depleted cells INSIG1 itself is ubiquitinated at Lys-156/158 by gp78 and degraded, while unsaturated fatty acids stabilize it post-ubiquitination by blocking Ubxd8-mediated VCP recruitment; additionally, phosphorylation by PCK1 (Ser207) or succination by ADSL disrupts INSIG1-SCAP binding to activate lipogenic SREBPs in cancer; and beyond lipid homeostasis, INSIG1 mediates oxysterol-triggered PERK-eIF2α-ATF4 ER stress signaling, supports STING K27-ubiquitination and TBK1 recruitment for antiviral innate immunity (with the E3 ligase AMFR), and interacts with Dapk3 to promote tubular cell apoptosis in kidney injury.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INSIG1 is an ER-resident polytopic membrane protein that serves as the central sterol sensor governing cellular lipid homeostasis through the SCAP/SREBP and HMG CoA reductase axes [#0, #6]. It adopts a six-transmembrane topology with cytosolic N- and C-termini, most of the protein buried within the membrane [#2], and a conserved cytosolic-facing Asp-205 that is essential for both of its key binding activities [#9]. In sterol-replete cells INSIG1 binds the sterol-sensing domain of SCAP, retaining the SCAP/SREBP complex in the ER and blocking SREBP transport to the Golgi for proteolytic activation; the SCAP(Y298C) mutant escapes this retention [#0], and INSIG1 overexpression in vivo suppresses nuclear SREBP and the full lipogenic transcriptional program [#3]. The same Asp-205-dependent surface binds the sterol-sensing domain of HMG CoA reductase, but with the opposite outcome: INSIG1 bridges the reductase to the membrane E3 ligase gp78 and the AAA-ATPase VCP/p97 to drive its ubiquitin-proteasomal ERAD [#1, #5, #9]. The divergent fates of the two partners — ER retention of SCAP versus degradation of reductase — arise because sterol-induced SCAP binding displaces gp78 from INSIG1, protecting it from ubiquitination [#8]. In sterol-depleted cells INSIG1 itself is ubiquitinated on Lys-156/158 and degraded, completing a feedback loop in which the INSIG1 gene is an SREBP target [#7]; unsaturated fatty acids stabilize ubiquitinated INSIG1 by blocking Ubxd8-mediated VCP recruitment and membrane extraction, a step distinct from the sterol block on ubiquitination [#10, #23]. INSIG1 abundance is thus a rheostat: its loss under hypotonic or ER stress bypasses sterol inhibition of SREBP processing [#4], and oncogenic signals override it — PCK1 phosphorylates INSIG1 at Ser207 and ADSL succinates it, both disrupting the INSIG-SCAP interaction to activate lipogenic SREBPs in hepatocellular carcinoma [#15, #19], while TRIM25 ubiquitinates INSIG1 to enhance SREBP nuclear translocation in metabolic liver disease [#18]. Beyond lipid control, INSIG1 functions as a scaffold in innate immunity, recruiting the E3 ligase AMFR to STING to catalyze K27-linked polyubiquitination and TBK1 recruitment for antiviral signaling [#13], and it mediates oxysterol-triggered PERK-eIF2\\u03b1-ATF4 ER stress and cell-death signaling [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established INSIG1 as the missing sterol-dependent retention factor that explains how high sterols keep SREBP inactive, by identifying its sterol-regulated binding to the SCAP sterol-sensing domain.\",\n      \"evidence\": \"Co-IP, mass spectrometry, blue native-PAGE, and SCAP(Y298C) functional mutant in cultured cells\",\n      \"pmids\": [\"12202038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how the same protein could produce opposite fates for different sterol-sensing-domain partners\", \"No structural model of the sterol-INSIG1 interface\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed the second arm of INSIG1 function — sterol-dependent binding to HMG CoA reductase that triggers its proteasomal degradation — and showed SCAP and reductase compete for the same INSIG1 site, defining a shared regulatory hub.\",\n      \"evidence\": \"Co-IP, proteasome inhibitor assays, and competition with overexpressed SCAP sterol-sensing domain\",\n      \"pmids\": [\"12535518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the E3 ligase and dislocation machinery not yet known\", \"Mechanism dictating retention vs. degradation unexplained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the membrane architecture of INSIG1 as a six-transmembrane protein with cytosolic termini, providing the topological framework for interpreting its binding and PTM sites.\",\n      \"evidence\": \"Protease protection, glycosylation site mapping, and cysteine derivatization\",\n      \"pmids\": [\"14660594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure\", \"Location of the sterol-binding pocket not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated in vivo that INSIG1 dosage controls the entire lipogenic transcriptional program, and that its abundance is acutely regulated — stress-induced loss of INSIG1 alone bypasses sterol inhibition of SREBP.\",\n      \"evidence\": \"Transgenic mouse liver overexpression with lipid/mRNA readouts, and hypotonic/thapsigargin stress with protein-synthesis inhibition in cells\",\n      \"pmids\": [\"15085196\", \"15304479\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of INSIG1 turnover and degradation not yet defined\", \"Why Insig-2 is spared was attributed to turnover rate without molecular detail\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified gp78 and VCP/p97 as the ubiquitination-extraction machinery INSIG1 recruits, and proved via double-knockout cells that INSIG proteins are absolutely required for all sterol regulation of SREBP and reductase.\",\n      \"evidence\": \"Co-IP and siRNA of gp78 with ubiquitination assays; SRD-15 Insig1/2-double-deficient CHO cells with complementation rescue\",\n      \"pmids\": [\"16168377\", \"15866869\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Insig-1 vs Insig-2 functional redundancy not separated in vivo\", \"Did not address INSIG1's own degradation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the central paradox of INSIG1 dual function: sterol depletion triggers gp78-mediated ubiquitination of INSIG1 at Lys-156/158 and its degradation, while sterol-induced SCAP binding displaces gp78 to stabilize INSIG1, and the conserved Asp-205 is required for both SCAP and reductase binding.\",\n      \"evidence\": \"Lys156/158 and Asp205Ala mutagenesis, ubiquitination and pulse-chase assays, gp78 siRNA, and SREBP/reductase functional readouts\",\n      \"pmids\": [\"16399501\", \"17043353\", \"16606821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic basis for sterol-induced gp78 displacement not resolved\", \"Whether the feedback loop fully accounts for INSIG1 oscillation in vivo untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Uncovered a second, lipid-class-specific layer of INSIG1 regulation — unsaturated fatty acids stabilize ubiquitinated INSIG1 by blocking Ubxd8-dependent VCP recruitment and membrane extraction, separating ubiquitination from dislocation.\",\n      \"evidence\": \"Ubiquitination and membrane extraction assays with Ubxd8/VCP Co-IP under fatty acid treatment\",\n      \"pmids\": [\"18835813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fatty acid signal is sensed at the membrane unclear\", \"Physiological context of this stabilization in vivo not established here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Ordered the ERAD steps mechanistically, showing INSIG1 is dislocated to the cytosol as an intact polytopic protein, that p97/VCP recruits proteasomes to membrane-embedded INSIG1 prior to extraction, and that a single residue (Leu-210 in Insig-2) sets the degradation rate.\",\n      \"evidence\": \"Cytosolic fractionation, p97/VCP inhibition, energy depletion, Insig-2 L210A mutagenesis, and proteasome Co-IP with membrane substrate\",\n      \"pmids\": [\"19458199\", \"19815544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural mechanism of polytopic dislocation unknown\", \"Single-lab evidence for pre-extraction proteasome recruitment\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Reconstituted lipid-regulated INSIG1 ERAD in a heterologous Drosophila system, confirming that sterols and unsaturated fatty acids inhibit degradation at distinct steps and that INSIG1 and reductase use different ligase complexes.\",\n      \"evidence\": \"Reconstitution in Drosophila S2 cells with genetic and pharmacological dissection plus fractionation\",\n      \"pmids\": [\"23403031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact ligase complement in mammalian cells partly contested (see gp78 reassessment)\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reassessed the E3 ligase requirement using gp78-knockout MEFs, finding gp78 needed for INSIG1 degradation but not for robust sterol-accelerated reductase degradation, contradicting the earlier reductase model.\",\n      \"evidence\": \"gp78 knockout MEFs and RNAi with INSIG1 and reductase degradation assays\",\n      \"pmids\": [\"23087214\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Source of discrepancy with prior gp78/reductase work unresolved\", \"Alternative reductase ligase not identified here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended INSIG1 beyond lipid metabolism by showing it is required to recruit the E3 ligase AMFR to STING for K27-linked ubiquitination and TBK1-dependent antiviral signaling.\",\n      \"evidence\": \"Co-IP, knockdown, myeloid-specific Insig1 KO mice, and HSV-1 infection model\",\n      \"pmids\": [\"25526307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How INSIG1 toggles between lipid and immune scaffolding roles unknown\", \"Whether sterol status modulates the STING function untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified an additional antiviral role in which INSIG1 partners with TRC8 to route HIV-1 Gag to lysosomal degradation, distinct from the proteasomal reductase pathway.\",\n      \"evidence\": \"Pseudovirus assays, knockouts, and proteasome-vs-lysosome inhibitor pharmacology\",\n      \"pmids\": [\"30563842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct INSIG1-Gag interaction not biochemically resolved\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked INSIG1 to ER stress and protective metabolic programs, showing it mediates oxysterol-dependent PERK-eIF2\\u03b1-ATF4 activation and that Insig1 loss in vivo remodels the hepatic lipidome to reduce lipotoxic liver damage.\",\n      \"evidence\": \"INSIG1/2-deficient cells with rescue and PERK pathway inhibitors; Insig1 KO mice on NASH diet with lipidomics\",\n      \"pmids\": [\"34298014\", \"33722690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct oxysterol-INSIG1 sensing in PERK activation not structurally defined\", \"Mechanism connecting SREBP hyperactivation to hepatoprotection incomplete\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that oncogenic signaling overrides INSIG1 sterol gating: PCK1 phosphorylates INSIG1 at Ser207 to reduce sterol binding and release SCAP-SREBP for lipogenesis in HCC.\",\n      \"evidence\": \"In vitro kinase assays, Ser207 mutagenesis, Co-IP, fractionation, and xenograft tumorigenesis\",\n      \"pmids\": [\"32322062\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether phosphorylation also alters INSIG1 degradation kinetics not addressed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Expanded the post-translational control of INSIG1 in disease, showing TRIM25-mediated ubiquitination, ADSL-mediated succination, and cholesterol-enhanced NFE2L1 binding each disrupt INSIG1 to activate SREBP-driven lipogenesis or VLDL secretion.\",\n      \"evidence\": \"Co-IP, PTM mapping, domain mutagenesis, knockout mice, and pharmacological inhibitors across MASH/HCC/VLDL models\",\n      \"pmids\": [\"40231613\", \"41833955\", \"bio_10.1101_2025.06.09.657856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy and crosstalk among these competing PTM/binding events unknown\", \"NFE2L1 finding is a preprint\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Revealed a metabolism-independent role in which INSIG1 binds and stabilizes Dapk3 to promote tubular cell death in acute kidney injury.\",\n      \"evidence\": \"Proteomics interaction screen, conditional tubular Insig1 KO mice in cisplatin and I/R AKI, and Dapk3 inhibitor\",\n      \"pmids\": [\"42144057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct INSIG1-Dapk3 binding interface not mapped\", \"Whether sterol sensing contributes is unaddressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How INSIG1 partitions among its competing roles — sterol gating of SCAP, reductase ERAD targeting, immune and apoptotic scaffolding — and how its many PTMs are hierarchically integrated remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of INSIG1 with sterol or partners\", \"No unified model coordinating phosphorylation, succination, and ubiquitination\", \"Tissue-specific selection among lipid vs. non-lipid functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 13]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5, 7, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\"SCAP/SREBP-INSIG1 complex\", \"INSIG1-gp78-VCP ERAD complex\", \"AMFR/INSIG1-STING complex\"],\n    \"partners\": [\"SCAP\", \"HMGCR\", \"AMFR\", \"VCP\", \"FAF2\", \"STING1\", \"PCK1\", \"DAPK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}