Affinage

INSIG1

Insulin-induced gene 1 protein · UniProt O15503

Length
277 aa
Mass
30.0 kDa
Annotated
2026-06-10
64 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2002 High

    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

    PMID:12202038

    Open questions at the time
    • 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
  2. 2003 High

    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

    PMID:12535518

    Open questions at the time
    • Identity of the E3 ligase and dislocation machinery not yet known
    • Mechanism dictating retention vs. degradation unexplained
  3. 2003 High

    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

    PMID:14660594

    Open questions at the time
    • No high-resolution structure
    • Location of the sterol-binding pocket not mapped
  4. 2004 Medium

    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

    PMID:15085196 PMID:15304479

    Open questions at the time
    • Mechanism of INSIG1 turnover and degradation not yet defined
    • Why Insig-2 is spared was attributed to turnover rate without molecular detail
  5. 2005 High

    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

    PMID:15866869 PMID:16168377

    Open questions at the time
    • Insig-1 vs Insig-2 functional redundancy not separated in vivo
    • Did not address INSIG1's own degradation
  6. 2006 High

    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

    PMID:16399501 PMID:16606821 PMID:17043353

    Open questions at the time
    • Atomic basis for sterol-induced gp78 displacement not resolved
    • Whether the feedback loop fully accounts for INSIG1 oscillation in vivo untested
  7. 2008 High

    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

    PMID:18835813

    Open questions at the time
    • How fatty acid signal is sensed at the membrane unclear
    • Physiological context of this stabilization in vivo not established here
  8. 2009 Medium

    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

    PMID:19458199 PMID:19815544

    Open questions at the time
    • Structural mechanism of polytopic dislocation unknown
    • Single-lab evidence for pre-extraction proteasome recruitment
  9. 2013 High

    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

    PMID:23403031

    Open questions at the time
    • Exact ligase complement in mammalian cells partly contested (see gp78 reassessment)
  10. 2012 Medium

    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

    PMID:23087214

    Open questions at the time
    • Source of discrepancy with prior gp78/reductase work unresolved
    • Alternative reductase ligase not identified here
  11. 2014 High

    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

    PMID:25526307

    Open questions at the time
    • How INSIG1 toggles between lipid and immune scaffolding roles unknown
    • Whether sterol status modulates the STING function untested
  12. 2018 Medium

    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

    PMID:30563842

    Open questions at the time
    • Direct INSIG1-Gag interaction not biochemically resolved
    • Single-lab finding
  13. 2021 Medium

    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

    PMID:33722690 PMID:34298014

    Open questions at the time
    • Direct oxysterol-INSIG1 sensing in PERK activation not structurally defined
    • Mechanism connecting SREBP hyperactivation to hepatoprotection incomplete
  14. 2020 High

    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

    PMID:32322062

    Open questions at the time
    • Whether phosphorylation also alters INSIG1 degradation kinetics not addressed
  15. 2026 Medium

    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

    PMID:40231613 PMID:41833955 PMID:bio_10.1101_2025.06.09.657856

    Open questions at the time
    • Hierarchy and crosstalk among these competing PTM/binding events unknown
    • NFE2L1 finding is a preprint
  16. 2026 Medium

    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

    PMID:42144057

    Open questions at the time
    • Direct INSIG1-Dapk3 binding interface not mapped
    • Whether sterol sensing contributes is unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140299 molecular sensor activity 3 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 1 R-HSA-8953897 Cellular responses to stimuli 1
Partners
AMFRDAPK3FAF2HMGCRPCK1SCAPSTING1VCP
Complex memberships
AMFR/INSIG1-STING complexINSIG1-gp78-VCP ERAD complexSCAP/SREBP-INSIG1 complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 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. Coimmunoprecipitation, tandem mass spectrometry, blue native-PAGE, mutant SCAP(Y298C) functional analysis Cell High 12202038
2003 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). Coimmunoprecipitation, proteasome inhibitor assays, competitive binding with SCAP sterol-sensing domain overexpression Molecular cell High 12535518
2003 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. Protease protection assay, glycosylation site mapping, cysteine derivatization The Journal of biological chemistry High 14660594
2004 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. Transgenic mouse overexpression, nuclear SREBP quantification, lipid measurements, mRNA analysis The Journal of clinical investigation High 15085196
2004 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. Hypotonic shock and thapsigargin treatment, protein synthesis inhibition, immunoblotting, SREBP processing assays The Journal of biological chemistry Medium 15304479
2005 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. Coimmunoprecipitation, siRNA knockdown of gp78, ubiquitination assays, reductase degradation assays Molecular cell High 16168377
2005 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. Gamma-irradiation mutagenesis, 25-hydroxycholesterol selection, genetic complementation The Journal of biological chemistry High 15866869
2006 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. Site-directed mutagenesis of Lys156/158, ubiquitination assays, proteasome inhibitor experiments, pulse-chase analysis Cell metabolism High 16399501
2006 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. Coimmunoprecipitation, siRNA knockdown of gp78, sterol-regulated degradation assays The Journal of biological chemistry High 17043353
2006 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. Site-directed mutagenesis (Asp205Ala), coimmunoprecipitation, SREBP processing assay, reductase degradation assay Proceedings of the National Academy of Sciences of the United States of America High 16606821
2008 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. Ubiquitination assays, membrane extraction assays, coimmunoprecipitation of Ubxd8 and VCP with Insig-1, fatty acid treatment The Journal of biological chemistry High 18835813
2009 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. Cytosolic fractionation, coimmunoprecipitation, p97/VCP functional inhibition, metabolic energy depletion Molecular biology of the cell Medium 19458199
2009 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. Site-directed mutagenesis (Insig-2 L210A), coimmunoprecipitation of proteasomes with membrane-embedded Insig, pulse-chase degradation assays The Journal of biological chemistry High 19815544
2014 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. Coimmunoprecipitation, siRNA/shRNA knockdown, Insig1 conditional knockout mice, antiviral gene induction assays, HSV-1 infection model Immunity High 25526307
2018 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. Pseudovirus production assays, protein overexpression, gene knockouts, pathway inhibitor assays distinguishing proteasome vs. lysosome The Journal of biological chemistry Medium 30563842
2020 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. In vitro kinase assays, site-directed mutagenesis (Ser207 of INSIG1), coimmunoprecipitation, subcellular fractionation, mouse xenograft tumorigenesis models Nature High 32322062
2021 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). INSIG1/2-deficient cell lines, rescue re-expression, PERK/eIF2α pathway inhibitors, siRNA knockdown of INSIG1 or INSIG2 in Huh7 cells The Journal of biological chemistry Medium 34298014
2021 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. Insig1 knockout mouse model, NASH diet challenge, lipidomics, liver injury markers Molecular metabolism Medium 33722690
2025 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. TRIM25 knockout mice, Co-IP, ubiquitination assays, pharmacological TRIM25 inhibitor, MASH mouse model Advanced science Medium 40231613
2026 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. Proximity ligation, Co-IP, mass spectrometry identification of succination sites, PKCε inhibition/activation, ADSL-ER translocation assays, mouse tumorigenesis model Nature communications Medium 41833955
2026 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. Coimmunoprecipitation, domain mutagenesis (ΔNHB2), NFE2L1-deficient mice, lipidomics, VLDL secretion assays bioRxivpreprint Medium bio_10.1101_2025.06.09.657856
2026 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. Proteomics identification of Insig1-interacting proteins, conditional tubular Insig1 KO mice (cisplatin and I/R AKI models), siRNA knockdown, Dapk3 inhibitor (HS148) Journal of advanced research Medium 42144057
2012 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. gp78 knockout mouse embryonic fibroblasts, RNAi in fibroblast cell lines, reductase and Insig-1 degradation assays Molecular biology of the cell Medium 23087214
2013 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. Reconstitution of mammalian Insig-1 ERAD in Drosophila S2 cells, genetic manipulations, pharmacological inhibitors, subcellular fractionation Journal of lipid research High 23403031

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 835 12202038
2005 Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase. Molecular cell 314 16168377
2014 The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity 312 25526307
2003 Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain. Molecular cell 312 12535518
2020 The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 293 32322062
2004 Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis. The Journal of clinical investigation 238 15085196
2006 Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell metabolism 207 16399501
2004 Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. The Journal of biological chemistry 162 15304479
2006 Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78. The Journal of biological chemistry 139 17043353
2008 Regulatory cross-talk between drug metabolism and lipid homeostasis: constitutive androstane receptor and pregnane X receptor increase Insig-1 expression. Molecular pharmacology 134 18187584
2003 Insig-1 "brakes" lipogenesis in adipocytes and inhibits differentiation of preadipocytes. Proceedings of the National Academy of Sciences of the United States of America 110 12869692
2004 Hepatic insig-1 or -2 overexpression reduces lipogenesis in obese Zucker diabetic fatty rats and in fasted/refed normal rats. Proceedings of the National Academy of Sciences of the United States of America 98 15096598
2004 Rosiglitazone induction of Insig-1 in white adipose tissue reveals a novel interplay of peroxisome proliferator-activated receptor gamma and sterol regulatory element-binding protein in the regulation of adipogenesis. The Journal of biological chemistry 89 15073165
2003 Membrane topology of human insig-1, a protein regulator of lipid synthesis. The Journal of biological chemistry 85 14660594
2008 Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step. The Journal of biological chemistry 81 18835813
2013 Adaptive changes of the Insig1/SREBP1/SCD1 set point help adipose tissue to cope with increased storage demands of obesity. Diabetes 76 23919961
2023 A novel protein encoded by circINSIG1 reprograms cholesterol metabolism by promoting the ubiquitin-dependent degradation of INSIG1 in colorectal cancer. Molecular cancer 73 37087475
2002 The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP. Proceedings of the National Academy of Sciences of the United States of America 70 12242342
2005 Isolation of sterol-resistant Chinese hamster ovary cells with genetic deficiencies in both Insig-1 and Insig-2. The Journal of biological chemistry 65 15866869
2012 Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. Molecular biology of the cell 63 23087214
2016 MiR-145 Regulates Lipogenesis in Goat Mammary Cells Via Targeting INSIG1 and Epigenetic Regulation of Lipid-Related Genes. Journal of cellular physiology 53 27448180
1997 Cloning, human chromosomal assignment, and adipose and hepatic expression of the CL-6/INSIG1 gene. Genomics 52 9268630
2004 Isolation of mutant cells lacking Insig-1 through selection with SR-12813, an agent that stimulates degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. The Journal of biological chemistry 50 15247248
2010 Gene-gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics. The pharmacogenomics journal 47 20877301
2016 MicroRNA-26a/b and their host genes synergistically regulate triacylglycerol synthesis by targeting the INSIG1 gene. RNA biology 44 27002347
2006 Juxtamembranous aspartic acid in Insig-1 and Insig-2 is required for cholesterol homeostasis. Proceedings of the National Academy of Sciences of the United States of America 43 16606821
2020 Disruption of Dhcr7 and Insig1/2 in cholesterol metabolism causes defects in bone formation and homeostasis through primary cilium formation. Bone research 42 31934493
2009 Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation. Molecular biology of the cell 38 19458199
2021 Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression. Molecular metabolism 37 33722690
2009 INSIG1 influences obesity-related hypertriglyceridemia in humans. Journal of lipid research 36 19965593
2021 Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression. JCI insight 35 34622799
2013 Scavenger receptor CD36 mediates inhibition of cholesterol synthesis via activation of the PPARγ/PGC-1α pathway and Insig1/2 expression in hepatocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 24371122
2020 Emerging role of Insig-1 in lipid metabolism and lipid disorders. Clinica chimica acta; international journal of clinical chemistry 34 32461046
2011 Overexpression of Insig-1 protects β cell against glucolipotoxicity via SREBP-1c. Journal of biomedical science 29 21843373
2009 Regulated endoplasmic reticulum-associated degradation of a polytopic protein: p97 recruits proteasomes to Insig-1 before extraction from membranes. The Journal of biological chemistry 29 19815544
2020 High rumen degradable starch decreased goat milk fat via trans-10, cis-12 conjugated linoleic acid-mediated downregulation of lipogenesis genes, particularly, INSIG1. Journal of animal science and biotechnology 25 32280461
2020 Effect of INSIG1 on the milk fat synthesis of buffalo mammary epithelial cells. The Journal of dairy research 20 32907640
2022 Tim-4 reprograms cholesterol metabolism to suppress antiviral innate immunity by disturbing the Insig1-SCAP interaction in macrophages. Cell reports 19 36450259
2020 CRISPR/Cas9 Based Knockout of miR-145 Affects Intracellular Fatty Acid Metabolism by Targeting INSIG1 in Goat Mammary Epithelial Cells. Journal of agricultural and food chemistry 17 32299216
2019 MicroRNAs Involved in the Regulation of LC-PUFA Biosynthesis in Teleosts: miR-33 Enhances LC-PUFA Biosynthesis in Siganus canaliculatus by Targeting insig1 which in Turn Upregulates srebp1. Marine biotechnology (New York, N.Y.) 14 31020472
2021 The Propensity of the Human Liver to Form Large Lipid Droplets Is Associated with PNPLA3 Polymorphism, Reduced INSIG1 and NPC1L1 Expression and Increased Fibrogenetic Capacity. International journal of molecular sciences 13 34198853
2013 Lipid-regulated degradation of HMG-CoA reductase and Insig-1 through distinct mechanisms in insect cells. Journal of lipid research 13 23403031
2016 Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner. The pharmacogenomics journal 11 26927283
2008 The INSIG1 gene, not the INSIG2 gene, associated with coronary heart disease: tagSNPs and haplotype-based association study. The Beijing Atherosclerosis Study. Thrombosis and haemostasis 11 18989534
2007 Amplification of the gene for SCAP, coupled with Insig-1 deficiency, confers sterol resistance in mutant Chinese hamster ovary cells. Journal of lipid research 11 17586788
2018 miR-122 Regulates LHR Expression in Rat Granulosa Cells by Targeting Insig1 mRNA. Endocrinology 9 29579170
2024 Hepatic miR-363 promotes nonalcoholic fatty liver disease by suppressing INSIG1. The Journal of nutritional biochemistry 8 39103107
2021 Insulin-induced genes INSIG1 and INSIG2 mediate oxysterol-dependent activation of the PERK-eIF2α-ATF4 axis. The Journal of biological chemistry 8 34298014
2013 Isolation, sequence characterization, and tissue transcription profiles of two novel buffalo genes: INSIG1 and INSIG2. Tropical animal health and production 7 23860946
2010 No association between polymorphisms in the INSIG1 gene and the risk of type 2 diabetes and related traits. The American journal of clinical nutrition 7 20444954
2025 TRIM25-Mediated INSIG1 Ubiquitination Promotes MASH Progression Through Reprogramming Lipid Metabolism. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 6 40231613
2018 Insulin-induced gene 1 (INSIG1) inhibits HIV-1 production by degrading Gag via activity of the ubiquitin ligase TRC8. The Journal of biological chemistry 6 30563842
2023 Fatty Acid Desaturation Is Suppressed in Mir-26a/b Knockout Goat Mammary Epithelial Cells by Upregulating INSIG1. International journal of molecular sciences 5 37373175
2017 Precursor microRNA-122 inhibits synthesis of Insig1 isoform mRNA by modulating polyadenylation site usage. RNA (New York, N.Y.) 5 28928276
2025 YY1/INSIG1 enhances atherosclerosis progression by regulating AMPK-mTOR signaling. Molecular immunology 4 40815888
2024 Single-Cell Sequencing and Machine Learning Integration to Identify Candidate Biomarkers in Psoriasis: INSIG1. Journal of inflammation research 3 39735895
2012 Haplotype combination of the bovine INSIG1 gene sequence variants and association with growth traits in Nanyang cattle. Genome 3 22642648
2008 [Effect of different glucose concentrations on the expressions of insig-1 and insig-2 mRNA during the differentiation of 3T3-L1 cells]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 2 18382059
2026 INSIG1 parallel substitution drives lipid/sterol metabolic plasticity mediating desert adaptation in ungulates. Communications biology 1 41526656
2018 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. DNA and cell biology 1 29356579
2026 INSIG1/2 succination mediated by the moonlighting function of ADSL promotes lipogenesis and liver tumorigenesis. Nature communications 0 41833955
2026 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. Toxics 0 42043177
2026 Insig1 deficiency protects against acute kidney injury via targeting Dapk3. Journal of advanced research 0 42144057
2024 Circular RNA_015343 sponges microRNA-25 to regulate viability, proliferation, and milk fat synthesis of ovine mammary epithelial cells via INSIG1. Journal of cellular physiology 0 38828915

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