INSI2_MOUSE
ID INSI2_MOUSE Reviewed; 225 AA.
AC Q91WG1; Q3TMY2; Q8BWP1;
DT 15-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 126.
DE RecName: Full=Insulin-induced gene 2 protein {ECO:0000303|PubMed:12242332};
DE Short=INSIG-2 {ECO:0000303|PubMed:12242332};
GN Name=Insig2 {ECO:0000303|PubMed:12242332, ECO:0000312|MGI:MGI:1920249};
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], FUNCTION, AND INTERACTION WITH SCAP AND SREBP2
RP COMPLEX.
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=C3H/HeJ, C57BL/6J, and NOD;
RC TISSUE=Aorta, Bone marrow, Brain, Dendritic cell, Liver, and Testis;
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 STRAIN=FVB/N; TISSUE=Eye, Kidney, and Mammary tumor;
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 FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=12624180; DOI=10.1073/pnas.0130116100;
RA Yabe D., Komuro R., Liang G., Goldstein J.L., Brown M.S.;
RT "Liver-specific mRNA for Insig-2 down-regulated by insulin: implications
RT for fatty acid synthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:3155-3160(2003).
RN [5]
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 [6]
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 [7]
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 [8]
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:12242332,
CC PubMed:12624180, PubMed:16100574). Acts as a negative regulator of
CC cholesterol biosynthesis by mediating the retention of the SCAP-SREBP
CC complex in the endoplasmic reticulum, thereby blocking the processing
CC of sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1
CC and SREBF2/SREBP2 (PubMed:16100574). Binds oxysterol, including 22-
CC hydroxycholesterol, 24-hydroxycholesterol, 25-hydroxycholesterol and
CC 27-hydroxycholesterol, regulating interaction with SCAP and retention
CC of the SCAP-SREBP complex in the endoplasmic reticulum (By similarity).
CC In presence of oxysterol, interacts with SCAP, retaining the SCAP-SREBP
CC complex in the endoplasmic reticulum, thereby preventing SCAP from
CC escorting SREBF1/SREBP1 and SREBF2/SREBP2 to the Golgi (By similarity).
CC Sterol deprivation or phosphorylation by PCK1 reduce oxysterol-binding,
CC disrupting the interaction between INSIG2 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 ligase RNF139 (By
CC similarity). {ECO:0000250|UniProtKB:Q9Y5U4,
CC ECO:0000269|PubMed:12242332, ECO:0000269|PubMed:12624180,
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 RNF139. Interacts with
CC RNF145. {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q9Y5U4}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- TISSUE SPECIFICITY: Expressed in liver, testis, kidney, spleen,
CC intestine, brain and adrenal gland. {ECO:0000269|PubMed:12624180}.
CC -!- INDUCTION: Up-regulated in differentiating preadipocytes.
CC {ECO:0000269|PubMed:12869692}.
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 -!- DOMAIN: The KxHxx motif mediates association with the coatomer complex.
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- PTM: Phosphorylation at Ser-151 by PCK1 reduces binding to oxysterol,
CC disrupting the interaction between INSIG2 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:Q9Y5U4}.
CC -!- PTM: Polyubiquitinated by AMFR/gp78 at Cys-215 in some tissues such as
CC adipose tissues, undifferentiated myoblasts and liver, leading to its
CC degradation. In differentiated myotubes, Cys-215 oxidation prevents
CC ubiquitination at the same site, resulting in protein stabilization.
CC {ECO:0000250|UniProtKB:Q9Y5U4}.
CC -!- PTM: Oxidized at Cys-215 in differentiated myotubes, preventing
CC ubiquitination at the same site, and resulting in protein
CC stabilization. {ECO:0000250|UniProtKB:Q9Y5U4}.
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; AF527631; AAN28332.1; -; mRNA.
DR EMBL; AK161256; BAE36273.1; -; mRNA.
DR EMBL; AK154543; BAE32667.1; -; mRNA.
DR EMBL; AK152076; BAE30928.1; -; mRNA.
DR EMBL; AK050394; BAC34233.1; -; mRNA.
DR EMBL; AK165634; BAE38307.1; -; mRNA.
DR EMBL; AK040703; BAC30676.1; -; mRNA.
DR EMBL; BC024411; AAH24411.1; -; mRNA.
DR EMBL; BC023874; AAH23874.1; -; mRNA.
DR EMBL; BC023067; AAH23067.1; -; mRNA.
DR EMBL; BC015288; AAH15288.1; -; mRNA.
DR CCDS; CCDS15236.1; -.
DR RefSeq; NP_001258460.1; NM_001271531.1.
DR RefSeq; NP_598509.1; NM_133748.2.
DR RefSeq; NP_835183.1; NM_178082.3.
DR RefSeq; XP_006529952.1; XM_006529889.1.
DR RefSeq; XP_006529953.1; XM_006529890.3.
DR RefSeq; XP_006529954.1; XM_006529891.3.
DR RefSeq; XP_006529955.1; XM_006529892.1.
DR AlphaFoldDB; Q91WG1; -.
DR SMR; Q91WG1; -.
DR STRING; 10090.ENSMUSP00000003818; -.
DR iPTMnet; Q91WG1; -.
DR PhosphoSitePlus; Q91WG1; -.
DR SwissPalm; Q91WG1; -.
DR MaxQB; Q91WG1; -.
DR PaxDb; Q91WG1; -.
DR PRIDE; Q91WG1; -.
DR ProteomicsDB; 266994; -.
DR Antibodypedia; 55566; 123 antibodies from 26 providers.
DR Ensembl; ENSMUST00000003818; ENSMUSP00000003818; ENSMUSG00000003721.
DR Ensembl; ENSMUST00000071064; ENSMUSP00000065485; ENSMUSG00000003721.
DR Ensembl; ENSMUST00000159085; ENSMUSP00000124345; ENSMUSG00000003721.
DR Ensembl; ENSMUST00000160968; ENSMUSP00000123747; ENSMUSG00000003721.
DR GeneID; 72999; -.
DR KEGG; mmu:72999; -.
DR UCSC; uc007cjo.1; mouse.
DR CTD; 51141; -.
DR MGI; MGI:1920249; Insig2.
DR VEuPathDB; HostDB:ENSMUSG00000003721; -.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR HOGENOM; CLU_092922_0_0_1; -.
DR InParanoid; Q91WG1; -.
DR OMA; KHLGEPH; -.
DR OrthoDB; 1342554at2759; -.
DR PhylomeDB; Q91WG1; -.
DR TreeFam; TF331013; -.
DR BioGRID-ORCS; 72999; 1 hit in 75 CRISPR screens.
DR PRO; PR:Q91WG1; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; Q91WG1; protein.
DR Bgee; ENSMUSG00000003721; Expressed in interventricular septum and 252 other tissues.
DR ExpressionAtlas; Q91WG1; baseline and differential.
DR Genevisible; Q91WG1; 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; ISS:UniProtKB.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IBA:GO_Central.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IGI: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:0045717; P:negative regulation of fatty acid biosynthetic process; IGI:MGI.
DR GO; GO:0010894; P:negative regulation of steroid biosynthetic process; IGI:MGI.
DR GO; GO:0070542; P:response to fatty acid; IEA:Ensembl.
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; ISS:UniProtKB.
DR GO; GO:0036316; P:SREBP-SCAP complex retention in endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0016126; P:sterol biosynthetic process; IGI:MGI.
DR GO; GO:0006641; P:triglyceride metabolic process; IGI:MGI.
DR InterPro; IPR025929; INSIG_fam.
DR PANTHER; PTHR15301; PTHR15301; 1.
DR Pfam; PF07281; INSIG; 1.
PE 1: Evidence at protein level;
KW Cholesterol metabolism; Endoplasmic reticulum; Lipid metabolism;
KW Lipid-binding; Membrane; Oxidation; Phosphoprotein; Reference proteome;
KW Steroid metabolism; Sterol metabolism; Thioester bond; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..225
FT /note="Insulin-induced gene 2 protein"
FT /id="PRO_0000286798"
FT TOPO_DOM 1..28
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 29..51
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 52..70
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 71..88
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 89..103
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 104..126
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 127..129
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 130..148
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 149..153
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 154..175
FT /note="Helical; Name=5"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 176..189
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 190..207
FT /note="Helical; Name=6"
FT /evidence="ECO:0000250|UniProtKB:A1T557"
FT TOPO_DOM 208..225
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT MOTIF 219..225
FT /note="KxHxx"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT SITE 115
FT /note="Required for the recognition of 25-
FT hydroxycholesterol"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT MOD_RES 151
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT MOD_RES 215
FT /note="Cysteine sulfenic acid (-SOH); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT CROSSLNK 215
FT /note="Glycyl cysteine thioester (Cys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y5U4"
FT CONFLICT 98
FT /note="P -> H (in Ref. 2; BAC34233)"
FT /evidence="ECO:0000305"
FT CONFLICT 106
FT /note="S -> Y (in Ref. 2; BAE38307)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 225 AA; 24915 MW; 095F322846DA3CF9 CRC64;
MAEGETESPR PKKCGPYISS VTSQSVNVVI RGVVLFFIGV FLALVLNLLQ IQRNVTLFPP
DVITSIFSSA WWVPPCCGTA SAVIGLLYPC IDRHLGEPHK FKREWSSVMR CVAVFVGINH
ASAKVDFDNN FQFSLTLAAL SVGLWWTFDR SRSGFGLGVG IAFLATVVTQ LLVYNGVYQY
TSPDFLYVRS WLPCIFFAGG ITMGNIGRQL AMYECKVIAE KSHQE
