INSI1_RAT
ID INSI1_RAT Reviewed; 259 AA.
AC Q08755;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 123.
DE RecName: Full=Insulin-induced gene 1 protein {ECO:0000250|UniProtKB:O15503};
DE Short=INSIG-1 {ECO:0000250|UniProtKB:O15503};
DE AltName: Full=Immediate-early protein CL-6 {ECO:0000303|PubMed:7686911};
DE AltName: Full=Insulin-induced growth response protein CL-6 {ECO:0000303|PubMed:7686911};
GN Name=Insig1 {ECO:0000312|RGD:708457};
GN Synonyms=Cl-6 {ECO:0000303|PubMed:7686911};
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], TISSUE SPECIFICITY, AND INDUCTION.
RC TISSUE=Liver;
RX PubMed=7686911; DOI=10.1016/s0021-9258(18)82454-1;
RA Diamond R.H., Du K., Lee V.M., Mohn K.L., Haber B.A., Tewari D.S., Taub R.;
RT "Novel delayed-early and highly insulin-induced growth response genes.
RT Identification of HRS, a potential regulator of alternative pre-mRNA
RT splicing.";
RL J. Biol. Chem. 268:15185-15192(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
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 25-
CC hydroxycholesterol, regulating interaction with SCAP and retention of
CC 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 INSIG1 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 ligases AMFR/gp78 and/or RNF139. Also regulates degradation
CC of SOAT2/ACAT2 when the lipid levels are low: initiates the ubiquitin-
CC mediated degradation of SOAT2/ACAT2 via recruitment of the ubiquitin
CC ligases AMFR/gp78. {ECO:0000250|UniProtKB:O15503}.
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 -!- TISSUE SPECIFICITY: Highly expressed in liver and kidney.
CC {ECO:0000269|PubMed:7686911}.
CC -!- INDUCTION: By insulin and hepatectomy. {ECO:0000269|PubMed:7686911}.
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 -!- SIMILARITY: Belongs to the INSIG family. {ECO:0000305}.
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DR EMBL; L13619; AAA40938.1; -; mRNA.
DR EMBL; BC078827; AAH78827.1; -; mRNA.
DR PIR; A47112; A47112.
DR RefSeq; NP_071787.1; NM_022392.1.
DR AlphaFoldDB; Q08755; -.
DR SMR; Q08755; -.
DR STRING; 10116.ENSRNOP00000009233; -.
DR PaxDb; Q08755; -.
DR Ensembl; ENSRNOT00000009233; ENSRNOP00000009233; ENSRNOG00000006859.
DR GeneID; 64194; -.
DR KEGG; rno:64194; -.
DR CTD; 3638; -.
DR RGD; 708457; Insig1.
DR eggNOG; KOG4363; Eukaryota.
DR GeneTree; ENSGT00580000081600; -.
DR HOGENOM; CLU_092922_0_0_1; -.
DR InParanoid; Q08755; -.
DR OMA; FWSCSCT; -.
DR OrthoDB; 1342554at2759; -.
DR PhylomeDB; Q08755; -.
DR TreeFam; TF331013; -.
DR PRO; PR:Q08755; -.
DR Proteomes; UP000002494; Chromosome 4.
DR Bgee; ENSRNOG00000006859; Expressed in duodenum and 19 other tissues.
DR Genevisible; Q08755; RN.
DR GO; GO:0005783; C:endoplasmic reticulum; 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:0032869; P:cellular response to insulin stimulus; IEP:RGD.
DR GO; GO:0036315; P:cellular response to sterol; ISO:RGD.
DR GO; GO:0006695; P:cholesterol biosynthetic process; ISO:RGD.
DR GO; GO:0042632; P:cholesterol homeostasis; ISO:RGD.
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:1901303; P:negative regulation of cargo loading into COPII-coated vesicle; ISO:RGD.
DR GO; GO:0045599; P:negative regulation of fat cell differentiation; ISO:RGD.
DR GO; GO:0045717; P:negative regulation of fatty acid biosynthetic process; ISO:RGD.
DR GO; GO:0070862; P:negative regulation of protein exit from endoplasmic reticulum; ISO:RGD.
DR GO; GO:0010894; P:negative regulation of steroid biosynthetic process; ISO:RGD.
DR GO; GO:0032355; P:response to estradiol; IEP:RGD.
DR GO; GO:0070542; P:response to fatty acid; IEP:RGD.
DR GO; GO:0033993; P:response to lipid; IEP:RGD.
DR GO; GO:0043434; P:response to peptide hormone; 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; ISO:RGD.
DR GO; GO:0036316; P:SREBP-SCAP complex retention in endoplasmic reticulum; ISO:RGD.
DR GO; GO:0016126; P:sterol biosynthetic process; ISO:RGD.
DR GO; GO:0006641; P:triglyceride metabolic process; ISO:RGD.
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_0000191677"
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 33..57
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"
SQ SEQUENCE 259 AA; 28232 MW; 68DA7E609818F637 CRC64;
MPRLHDHVWS YPSAGAARPY SLPRGMIAAA LCPQGPGAPE PEPAPRGQRE GTAGFSARPG
SWHHDLVQRS LVLFSFGVVL ALVLNLLQIQ RNVTLFPDEV IATIFSSAWW VPPCCGTAAA
VVGLLYPCID SHLGEPHKFK REWASVMRCI AVFVGINHAS AKLDFANNVQ LSLTLAALSL
GLWWTFDRSR SGLGLGITIA FLATLITQFL VYNGVYQYTS PDFLYIRSWL PCIFFSGGVT
VGNIGRQLAM GVPEKPHSD
