ID INSI2_RAT Reviewed; 225 AA. AC Q80UA9; DT 15-MAY-2007, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2003, sequence version 1. DT 24-JAN-2024, entry version 106. DE RecName: Full=Insulin-induced gene 2 protein {ECO:0000303|PubMed:12624180}; DE Short=INSIG-2 {ECO:0000303|PubMed:12624180}; GN Name=Insig2 {ECO:0000303|PubMed:12624180, ECO:0000312|RGD:631417}; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND INDUCTION. 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 [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Heart; 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). 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. Acts as a negative CC regulator of cholesterol biosynthesis by mediating the retention of the CC SCAP-SREBP complex in the endoplasmic reticulum, thereby blocking the CC processing of sterol regulatory element-binding proteins (SREBPs) CC SREBF1/SREBP1 and SREBF2/SREBP2. 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. In presence of CC oxysterol, 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. Sterol deprivation or CC phosphorylation by PCK1 reduce oxysterol-binding, disrupting the CC interaction between INSIG2 and SCAP, thereby promoting Golgi transport CC of the SCAP-SREBP complex, followed by processing and nuclear CC translocation of SREBF1/SREBP1 and SREBF2/SREBP2. Also regulates CC cholesterol synthesis by regulating degradation of HMGCR: initiates the CC sterol-mediated ubiquitin-mediated endoplasmic reticulum-associated CC degradation (ERAD) of HMGCR via recruitment of the reductase to the CC ubiquitin ligase RNF139. {ECO:0000250|UniProtKB:Q9Y5U4}. 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 -!- 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 -!- SIMILARITY: Belongs to the INSIG family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AY152392; AAN78347.1; -; mRNA. DR EMBL; BC085682; AAH85682.1; -; mRNA. DR RefSeq; NP_835192.1; NM_178091.4. DR RefSeq; XP_006249729.1; XM_006249667.3. DR RefSeq; XP_006249730.1; XM_006249668.3. DR RefSeq; XP_006249731.1; XM_006249669.3. DR RefSeq; XP_017454176.1; XM_017598687.1. DR AlphaFoldDB; Q80UA9; -. DR SMR; Q80UA9; -. DR STRING; 10116.ENSRNOP00000003391; -. DR PhosphoSitePlus; Q80UA9; -. DR PaxDb; 10116-ENSRNOP00000003391; -. DR GeneID; 288985; -. DR KEGG; rno:288985; -. DR UCSC; RGD:631417; rat. DR AGR; RGD:631417; -. DR CTD; 51141; -. DR RGD; 631417; Insig2. DR VEuPathDB; HostDB:ENSRNOG00000002478; -. DR eggNOG; KOG4363; Eukaryota. DR HOGENOM; CLU_092922_0_0_1; -. DR InParanoid; Q80UA9; -. DR OrthoDB; 2943928at2759; -. DR PhylomeDB; Q80UA9; -. DR TreeFam; TF331013; -. DR PRO; PR:Q80UA9; -. DR Proteomes; UP000002494; Chromosome 13. DR Bgee; ENSRNOG00000002478; Expressed in liver and 18 other cell types or tissues. DR GO; GO:0005783; C:endoplasmic reticulum; ISO:RGD. DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISO:RGD. DR GO; GO:0032937; C:SREBP-SCAP-Insig complex; ISO:RGD. DR GO; GO:0008142; F:oxysterol binding; ISS:UniProtKB. DR GO; GO:0140311; F:protein sequestering activity; ISO:RGD. DR GO; GO:0032869; P:cellular response to insulin stimulus; IBA:GO_Central. DR GO; GO:0006695; P:cholesterol biosynthetic process; ISS:UniProtKB. DR GO; GO:0008203; P:cholesterol metabolic process; ISO:RGD. DR GO; GO:0060363; P:cranial suture morphogenesis; ISO:RGD. DR GO; GO:0042472; P:inner ear morphogenesis; ISO:RGD. DR GO; GO:0042474; P:middle ear morphogenesis; ISO:RGD. DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; ISO:RGD. DR GO; GO:0010894; P:negative regulation of steroid biosynthetic process; ISO:RGD. DR GO; GO:0070542; P:response to fatty acid; IEP:RGD. DR GO; GO:0032868; P:response to insulin; IEP:RGD. DR GO; GO:0033993; P:response to lipid; IEP:RGD. DR GO; GO:0006991; P:response to sterol depletion; ISO:RGD. DR GO; GO:0060021; P:roof of mouth development; ISO:RGD. 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; ISO:RGD. DR GO; GO:0006641; P:triglyceride metabolic process; ISO:RGD. DR InterPro; IPR025929; INSIG_fam. DR PANTHER; PTHR15301; INSULIN-INDUCED GENE 1; 1. DR PANTHER; PTHR15301:SF10; INSULIN-INDUCED GENE 2 PROTEIN; 1. DR Pfam; PF07281; INSIG; 1. DR Genevisible; Q80UA9; RN. PE 2: Evidence at transcript 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_0000286801" 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" SQ SEQUENCE 225 AA; 24968 MW; 534E933526CB2195 CRC64; MAEGETESPR PKKRGPYISS VTSQSVNVVI RGVVLFFIGV FLALVLNLLQ IQRNVTLFPP DVITSIFSSA WWVPPCCGTA SAVIGLLYPC IDRHLGEPHK FKREWSSVMR CVAVFVGINH ASAKVDFDNN FQFSLTLAAL SVGLWWTFDR SRSGFGLGVG IAFLATVVTQ LLVYNGVYQY TSPDFLYVRS WLPCIFFAGG ITMGNIGRQL AMYECKVIAE KSHQE //