INSI1_MOUSE
ID INSI1_MOUSE Reviewed; 259 AA.
AC Q8BGI3; A2RSM6; Q3UAX9; Q3UX30;
DT 12-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 126.
DE RecName: Full=Insulin-induced gene 1 protein {ECO:0000303|PubMed:12242332};
DE Short=INSIG-1 {ECO:0000303|PubMed:12242332};
GN Name=Insig1 {ECO:0000303|PubMed:12242332, ECO:0000312|MGI:MGI:1916289};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C57BL/6J X SJL;
RX PubMed=12242332; DOI=10.1073/pnas.162488899;
RA Yabe D., Brown M.S., Goldstein J.L.;
RT "Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks
RT export of sterol regulatory element-binding proteins.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:12753-12758(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J, and NOD; TISSUE=Bone marrow, Egg, and Thymus;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP INDUCTION.
RX PubMed=12869692; DOI=10.1073/pnas.1133426100;
RA Li J., Takaishi K., Cook W., McCorkle S.K., Unger R.H.;
RT "Insig-1 'brakes' lipogenesis in adipocytes and inhibits differentiation of
RT preadipocytes.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:9476-9481(2003).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=16100574; DOI=10.1172/jci25614;
RA Engelking L.J., Liang G., Hammer R.E., Takaishi K., Kuriyama H.,
RA Evers B.M., Li W.P., Horton J.D., Goldstein J.L., Brown M.S.;
RT "Schoenheimer effect explained--feedback regulation of cholesterol
RT synthesis in mice mediated by Insig proteins.";
RL J. Clin. Invest. 115:2489-2498(2005).
RN [6]
RP DISRUPTION PHENOTYPE.
RX PubMed=16955138; DOI=10.1172/jci28988;
RA Engelking L.J., Evers B.M., Richardson J.A., Goldstein J.L., Brown M.S.,
RA Liang G.;
RT "Severe facial clefting in Insig-deficient mouse embryos caused by sterol
RT accumulation and reversed by lovastatin.";
RL J. Clin. Invest. 116:2356-2365(2006).
RN [7]
RP REVIEW.
RX PubMed=28849786; DOI=10.1038/nrendo.2017.91;
RA Shimano H., Sato R.;
RT "SREBP-regulated lipid metabolism: convergent physiology - divergent
RT pathophysiology.";
RL Nat. Rev. Endocrinol. 13:710-730(2017).
CC -!- FUNCTION: Oxysterol-binding protein that mediates feedback control of
CC cholesterol synthesis by controlling both endoplasmic reticulum to
CC Golgi transport of SCAP and degradation of HMGCR (PubMed:16100574).
CC Acts as a negative regulator of cholesterol biosynthesis by mediating
CC the retention of the SCAP-SREBP complex in the endoplasmic reticulum,
CC thereby blocking the processing of sterol regulatory element-binding
CC proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2 (By similarity).
CC Binds oxysterol, including 25-hydroxycholesterol, regulating
CC interaction with SCAP and retention of the SCAP-SREBP complex in the
CC endoplasmic reticulum (PubMed:16100574). In presence of oxysterol,
CC interacts with SCAP, retaining the SCAP-SREBP complex in the
CC endoplasmic reticulum, thereby preventing SCAP from escorting
CC SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi (By similarity). Sterol
CC deprivation or phosphorylation by PCK1 reduce oxysterol-binding,
CC disrupting the interaction between INSIG1 and SCAP, thereby promoting
CC Golgi transport of the SCAP-SREBP complex, followed by processing and
CC nuclear translocation of SREBF1/SREBP1 and SREBF2/SREBP2 (By
CC similarity). Also regulates cholesterol synthesis by regulating
CC degradation of HMGCR: initiates the sterol-mediated ubiquitin-mediated
CC endoplasmic reticulum-associated degradation (ERAD) of HMGCR via
CC recruitment of the reductase to the ubiquitin ligases AMFR/gp78 and/or
CC RNF139 (By similarity). Also regulates degradation of SOAT2/ACAT2 when
CC the lipid levels are low: initiates the ubiquitin-mediated degradation
CC of SOAT2/ACAT2 via recruitment of the ubiquitin ligases AMFR/gp78 (By
CC similarity). {ECO:0000250|UniProtKB:O15503,
CC ECO:0000269|PubMed:16100574}.
CC -!- SUBUNIT: Interacts with SCAP; interaction is direct and only takes
CC place in the presence of sterols; it prevents interaction between SCAP
CC and the coat protein complex II (COPII). Associates with the SCAP-SREBP
CC complex (composed of SCAP and SREBF1/SREBP1 or SREBF2/SREBP2);
CC association is mediated via its interaction with SCAP and only takes
CC place in the presence of sterols. Interacts with HMGCR (via its SSD);
CC the interaction, accelerated by sterols, leads to the recruitment of
CC HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD
CC pathway. Interacts with AMFR/gp78 (via its membrane domain); the
CC interaction recruits HMCR at the ER membrane for its ubiquitination and
CC degradation by the sterol-mediated ERAD pathway. Interacts with
CC SOAT2/ACAT2; leading to promote recruitment of AMFR/gp78 and subsequent
CC ubiquitination of SOAT2/ACAT2. Interacts with RNF139. Interacts with
CC RNF145. {ECO:0000250|UniProtKB:O15503}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:O15503}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:O15503}.
CC -!- INDUCTION: Up-regulated progressively in the fat tissue as they develop
CC diet-induced obesity (PubMed:12869692). Up-regulated in differentiating
CC preadipocytes (PubMed:12869692). {ECO:0000269|PubMed:12869692}.
CC -!- DOMAIN: The KxHxx motif mediates association with the coatomer complex.
CC {ECO:0000250|UniProtKB:O15503}.
CC -!- DOMAIN: Binds oxysterols in a pocket within their transmembrane domains
CC and interacts with SCAP via transmembrane domains 3 and 4.
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- PTM: Phosphorylation at Ser-189 by PCK1 reduces binding to oxysterol,
CC disrupting the interaction between INSIG1 and SCAP, thereby promoting
CC nuclear translocation of SREBP proteins (SREBF1/SREBP1 or
CC SREBF2/SREBP2) and subsequent transcription of downstream lipogenesis-
CC related genes. {ECO:0000250|UniProtKB:O15503}.
CC -!- PTM: Ubiquitinated by AMFR/gp78 in response to sterol deprivation,
CC leading to its degradation: when the SCAP-SREBP complex becomes
CC dissociated from INSIG1, INSIG1 is then ubiquitinated and degraded in
CC proteasomes. Although ubiquitination is required for rapid INSIG1
CC degradation, it is not required for release of the SCAP-SREBP complex.
CC Ubiquitinated by RNF139. {ECO:0000250|UniProtKB:O15503}.
CC -!- DISRUPTION PHENOTYPE: Knockout mice with a conditional deletion of
CC Insig1 in the liver and a germline deletion of Insig2 overaccumulate
CC cholesterol and triglycerides in liver: despite this accumulation,
CC levels of nuclear sterol regulatory element-binding proteins (SREBPs)
CC are not reduced (PubMed:16100574). The amount of HMGCR is also
CC elevated, caused by impaired degradation of the enzyme
CC (PubMed:16100574). Knockout mice with a germline deletion of both
CC Insig1 and Insig2 die within one day of birth (PubMed:16100574,
CC PubMed:16955138). After 18.5 days of development, embryos lacking both
CC Insig1 and Insig2 show defects in midline facial development, ranging
CC from cleft palate to complete cleft face: middle and inner ear
CC structures are abnormal, but teeth and skeletons are normal
CC (PubMed:16955138). The livers and heads of embryos lacking both Insig1
CC and Insig2 overproduce sterols, causing a marked buildup of sterol
CC intermediates (PubMed:16955138). {ECO:0000269|PubMed:16100574,
CC ECO:0000269|PubMed:16955138}.
CC -!- SIMILARITY: Belongs to the INSIG family. {ECO:0000305}.
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DR EMBL; AF527630; AAN28331.1; -; mRNA.
DR EMBL; AK088380; BAC40316.1; -; mRNA.
DR EMBL; AK135941; BAE22733.1; -; mRNA.
DR EMBL; AK139913; BAE24179.1; -; mRNA.
DR EMBL; AK151186; BAE30185.1; -; mRNA.
DR EMBL; BC132167; AAI32168.1; -; mRNA.
DR EMBL; BC132499; AAI32500.1; -; mRNA.
DR CCDS; CCDS19142.1; -.
DR RefSeq; NP_705746.1; NM_153526.5.
DR AlphaFoldDB; Q8BGI3; -.
DR SMR; Q8BGI3; -.
DR STRING; 10090.ENSMUSP00000061877; -.
DR PhosphoSitePlus; Q8BGI3; -.
DR PaxDb; Q8BGI3; -.
DR PRIDE; Q8BGI3; -.
DR ProteomicsDB; 269228; -.
DR Antibodypedia; 33108; 223 antibodies from 21 providers.
DR DNASU; 231070; -.
DR Ensembl; ENSMUST00000059155; ENSMUSP00000061877; ENSMUSG00000045294.
DR GeneID; 231070; -.
DR KEGG; mmu:231070; -.
DR UCSC; uc012dtq.1; mouse.
DR CTD; 3638; -.
DR MGI; MGI:1916289; Insig1.
DR VEuPathDB; HostDB:ENSMUSG00000045294; -.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR HOGENOM; CLU_092922_0_0_1; -.
DR InParanoid; Q8BGI3; -.
DR OMA; FWSCSCT; -.
DR OrthoDB; 1342554at2759; -.
DR PhylomeDB; Q8BGI3; -.
DR TreeFam; TF331013; -.
DR BioGRID-ORCS; 231070; 4 hits in 74 CRISPR screens.
DR ChiTaRS; Insig1; mouse.
DR PRO; PR:Q8BGI3; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q8BGI3; protein.
DR Bgee; ENSMUSG00000045294; Expressed in epithelium of small intestine and 235 other tissues.
DR Genevisible; Q8BGI3; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; ISO:MGI.
DR GO; GO:0008142; F:oxysterol binding; ISO:MGI.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IBA:GO_Central.
DR GO; GO:0036315; P:cellular response to sterol; ISO:MGI.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IGI:MGI.
DR GO; GO:0042632; P:cholesterol homeostasis; ISO:MGI.
DR GO; GO:0008203; P:cholesterol metabolic process; IGI:MGI.
DR GO; GO:0060363; P:cranial suture morphogenesis; IGI:MGI.
DR GO; GO:0042472; P:inner ear morphogenesis; IGI:MGI.
DR GO; GO:0042474; P:middle ear morphogenesis; IGI:MGI.
DR GO; GO:1901303; P:negative regulation of cargo loading into COPII-coated vesicle; ISO:MGI.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; IDA:MGI.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; IGI:MGI.
DR GO; GO:0070862; P:negative regulation of protein exit from endoplasmic reticulum; ISO:MGI.
DR GO; GO:0010894; P:negative regulation of steroid biosynthetic process; IGI:MGI.
DR GO; GO:0006991; P:response to sterol depletion; IDA:MGI.
DR GO; GO:0060021; P:roof of mouth development; IGI:MGI.
DR GO; GO:0032933; P:SREBP signaling pathway; ISO:MGI.
DR GO; GO:0036316; P:SREBP-SCAP complex retention in endoplasmic reticulum; ISO:MGI.
DR GO; GO:0016126; P:sterol biosynthetic process; IGI:MGI.
DR GO; GO:0006641; P:triglyceride metabolic process; IGI:MGI.
DR InterPro; IPR009904; INSIG-1.
DR InterPro; IPR025929; INSIG_fam.
DR PANTHER; PTHR15301; PTHR15301; 1.
DR PANTHER; PTHR15301:SF11; PTHR15301:SF11; 1.
DR Pfam; PF07281; INSIG; 1.
PE 2: Evidence at transcript level;
KW Cholesterol metabolism; Endoplasmic reticulum; Isopeptide bond;
KW Lipid metabolism; Lipid-binding; Membrane; Phosphoprotein;
KW Reference proteome; Steroid metabolism; Sterol metabolism; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..259
FT /note="Insulin-induced gene 1 protein"
FT /id="PRO_0000191676"
FT TOPO_DOM 1..66
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT TRANSMEM 67..89
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 90..108
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 109..126
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 127..141
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 142..164
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 165..167
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 168..186
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 187..191
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT TRANSMEM 192..213
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 214..227
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 228..245
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 246..259
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT REGION 36..55
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 253..259
FT /note="KxHxx"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT SITE 153
FT /note="Required for the recognition of 25-
FT hydroxycholesterol"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT MOD_RES 189
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT CROSSLNK 138
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT CROSSLNK 140
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O15503"
FT CONFLICT 28
FT /note="A -> G (in Ref. 2; BAE22733)"
FT /evidence="ECO:0000305"
FT CONFLICT 63
FT /note="H -> Y (in Ref. 2; BAE22733)"
FT /evidence="ECO:0000305"
FT CONFLICT 199
FT /note="I -> N (in Ref. 2; BAE22733)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 259 AA; 28213 MW; 964AD1FAA8EE610D CRC64;
MPRLHDHVWN YPSAGAARPY SLPRGMIAAA ACPQGPGVPE PEHAPRGQRA GTTGCSARPG
SWHHDLVQRS LVLFSFGVVL ALVLNLLQIQ RNVTLFPDEV IATIFSSAWW VPPCCGTAAA
VVGLLYPCID SHLGEPHKFK REWASVMRCI AVFVGINHAS AKLDFANNVQ LSLTLAALSL
GLWWTFDRSR SGLGLGITIA FLATLITQFL VYNGVYQYTS PDFLYIRSWL PCIFFSGGVT
VGNIGRQLAM GVPEKPHSD
