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FLASH GENE

Symbol

INSIG1

contributors: mct - updated : 03-02-2017

HGNC name	insulin induced gene 1
HGNC id	6083

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	12.46 kb     6 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005542 6 - 3020 NP_005533 - 277 - 1997 9268630 NM_198336 6 - 2635 NP_938150 - 178 - 1997 9268630 NM_198337 4 - 2728 NP_938151 - 164 - 1997 9268630

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver       highly Lymphoid/Immune lymph node         Reproductive female system breast mammary gland     Skin/Tegument skin

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES		Hydrophilic
STRUCTURE

motifs/domains	two leucine-rich repeats domains (LRR)
	six transmembrane segments separated by five short luminal and cytosolic loops that range from approximately 5 to 16 amino acids

HOMOLOGY

interspecies

homolog to C.elegans y56a3a.29

Homologene

FAMILY

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endoplasmic reticulum

basic FUNCTION	facilitating the sterol-dependent ER retention of SCAP, there by playing a central role in cholesterol biosunthesis
	playing a role in regulating cholesterol concentration
	blocks proteolytic activation of sterol regulatory element-binding proteins (SREBFs), transcription factors that activate genes regulating cholesterol and fatty acid metabolism and possibly genes involved in glucose homeostasis
	regulating the proteolytic processing of membrane-bound sterol regulatory element-binding proteins (SREBPs), transcription factors activating the synthesis of cholesterol and fatty acids
	inhibited the lipid accumulation and free fatty acid (FFA) synthesis in a time-dependent manner
	cellular cholesterol levels are controlled by endoplasmic reticulum (ER) sterol sensing proteins, which include SCAP and INSIG1
	essential role of INSIG1, INSIG2 proteins in the sterol homeostasis of enterocytes
	AMFR and INSIG1, an E3 ubiquitin ligase complex, then catalyzed the K27-linked polyubiquitination of CISD2
	essential role of the ER proteins AMFR and INSIG1 in innate immunity, revealing an important missing link in the CISD2 signaling pathway

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

lipid/lipoprotein

signaling

a component

INTERACTION

DNA

RNA

small molecule

protein	binding SCAP, promoted by sterols, retaining the SCAP/SREBP complex in the ER and preventing it from moving to the Golgi for proteolytic processing
	binding the sterol sensing domain of HMGCR and accelerating its degradation
	binding to the ER enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, facilitating its ubiquitination and proteasomal degradation
	interacting with SREBF1 (INSIG1 degradation is necessary for SREBF complex release from ER and its subsequent proteolytic activation in Golgi)
	may play a critical role in protecting beta cells against glucolipotoxicity by regulating the expression of SREBP-1c
	suppressed the high glucose induced SREBP-1c mRNA and protein expression
	sterol-induced ubiquitination and proteasomal degradation of reductase is dictated by the complex interplay of at least four proteins: INSIG1, INSIG2, AMFR, and RNF139
	AMFR and RNF139 are implicated in the sterol-regulated degradation of HMG-CoA reductase and INSIG1 through ER-associated degradation (ERAD)
	gluconeogenic enzyme PCK1 phosphorylates INSIG1/INSIG2 for lipogenesis

cell & other

unsaturated fatty acids stabilize INSIG1 without affecting its ubiquitination

REGULATION

induced by

insulin

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --other   . cholesterol metabolic aberrations, induced through disruption of either DHCR7 or INSIG1 and INSIG2 , result in osteoblast differentiation abnormalities

Susceptibility

to coronary heart disease

Variant & Polymorphism SNP	rs9769826 of the INSIG1 gene was associated with coronary heart disease

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS