DegronMD - Q96RI1(NR1H4)

FUNCTION: Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'-AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down-regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit pro-inflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity). {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q62735, ECO:0000269|PubMed:10334992, ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:10514450, ECO:0000269|PubMed:11579204, ECO:0000269|PubMed:11927623, ECO:0000269|PubMed:12554753, ECO:0000269|PubMed:12660231, ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12754200, ECO:0000269|PubMed:12806625, ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:12891557, ECO:0000269|PubMed:14684751, ECO:0000269|PubMed:15239098, ECO:0000269|PubMed:15337761, ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:16269519, ECO:0000269|PubMed:16946559, ECO:0000269|PubMed:17895379, ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19085950, ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:21242261, ECO:0000269|PubMed:21804189, ECO:0000269|PubMed:23928191, ECO:0000305|PubMed:21383957, ECO:0000305|PubMed:22820415}.; FUNCTION: [Isoform 1]: Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}.; FUNCTION: [Isoform 2]: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA), NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}.; FUNCTION: [Isoform 3]: Promotes transcriptional activation of target genes NR0B2/SHP (inducible by unconjugated CDCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and IBAP; low activity for ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA); not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}.; FUNCTION: [Isoform 4]: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA), NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; most efficient isoform compared to isoforms 1 to 3; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191, ECO:0000269|PubMed:26888176}. 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GO - Biological processes (BP): bile acid metabolic process [GO:0008206]; bile acid signaling pathway [GO:0038183]; cell-cell junction assembly [GO:0007043]; cell differentiation [GO:0030154]; cellular glucose homeostasis [GO:0001678]; cellular response to bile acid [GO:1903413]; cellular response to fatty acid [GO:0071398]; cellular response to lipopolysaccharide [GO:0071222]; cellular response to organonitrogen compound [GO:0071417]; cellular triglyceride homeostasis [GO:0035356]; cholesterol homeostasis [GO:0042632]; defense response to bacterium [GO:0042742]; fatty acid homeostasis [GO:0055089]; histone H3-R17 methylation [GO:0034971]; inflammatory response [GO:0006954]; innate immune response [GO:0045087]; intracellular bile acid receptor signaling pathway [GO:0038185]; intracellular receptor signaling pathway [GO:0030522]; negative regulation of apoptotic process [GO:0043066]; negative regulation of I-kappaB kinase/NF-kappaB signaling [GO:0043124]; negative regulation of inflammatory response [GO:0050728]; negative regulation of interferon-gamma production [GO:0032689]; negative regulation of interleukin-1 production [GO:0032692]; negative regulation of interleukin-2 production [GO:0032703]; negative regulation of interleukin-6 production [GO:0032715]; negative regulation of monocyte chemotactic protein-1 production [GO:0071638]; negative regulation of NF-kappaB transcription factor activity [GO:0032088]; negative regulation of transcription by RNA polymerase II [GO:0000122]; negative regulation of tumor necrosis factor-mediated signaling pathway [GO:0010804]; negative regulation of tumor necrosis factor production [GO:0032720]; negative regulation of very-low-density lipoprotein particle remodeling [GO:0010903]; nitrogen catabolite activation of transcription from RNA polymerase II promoter [GO:0001080]; Notch signaling pathway [GO:0007219]; positive regulation of adipose tissue development [GO:1904179]; positive regulation of ammonia assimilation cycle [GO:2001250]; positive regulation of glutamate metabolic process [GO:2000213]; positive regulation of insulin receptor signaling pathway [GO:0046628]; positive regulation of insulin secretion involved in cellular response to glucose stimulus [GO:0035774]; positive regulation of interleukin-17 production [GO:0032740]; positive regulation of phosphatidic acid biosynthetic process [GO:1905695]; positive regulation of transcription, DNA-templated [GO:0045893]; positive regulation of transcription by RNA polymerase II [GO:0045944]; regulation of bile acid biosynthetic process [GO:0070857]; regulation of cholesterol metabolic process [GO:0090181]; regulation of insulin secretion involved in cellular response to glucose stimulus [GO:0061178]; regulation of low-density lipoprotein particle clearance [GO:0010988]; regulation of transcription, DNA-templated [GO:0006355]; regulation of transcription by RNA polymerase II [GO:0006357]; regulation of urea metabolic process [GO:0034255]; toll-like receptor 4 signaling pathway [GO:0034142]; toll-like receptor 9 signaling pathway [GO:0034162] View more >>

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GO - Cellular component (CC): View more >>

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Mutation	Sample	Cancer	Dataset	Degron hit	Class	Location	Type	Impact score
p.T257S	TCGA-B0-5097	KIRC	TCGA	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.1389
p.G240D	TCGA-D3-A2JC	SKCM	TCGA	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.1667
p.S252L	TCGA-EE-A2GB	SKCM	TCGA	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.2778
p.D242Y	TCGA-KQ-A41N	BLCA	TCGA	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.2222
p.E255D	TCGA-QF-A5YS	UCEC	TCGA	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.1944
p.R241C	TCGA-W3-AA1V	SKCM	TCGA	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.1944
p.P251T	DO225349	BRCA	ICGC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.3056
p.T247S	DO19370	KIRC	ICGC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation altering degron motif	0.6005
p.K241N	DO229036	LICA	ICGC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.1944
p.S242L	DO222683	MELA	ICGC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.2222
p.S242L	DO37417	SKCM	ICGC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.2222
p.E245D	DO52426	UCEC	ICGC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.3056
p.T241M	RF-48	stomach	COSMIC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation rewiring degron network	0.1944
p.K256Q	SW948	large intestine	COSMIC	VTSTT	DEG_SPOP_SBC_1	246:250	Mutation substituting flanking lysine	0.2778

DegronMD: protein-targeted degradation, mutation and drug response to degrons

NR1H4

UniProt ID: Q96RI1

Entrez ID: 9971

Protein name: Bile acid receptor (Farnesoid X-activated receptor) (Farnesol receptor HRR-1) (Nuclear receptor subfamily 1 group H member 4) (Retinoid X receptor-interacting protein 14) (RXR-interacting protein 14)

External links: UniprotKB HGNC RefSeq COSMIC

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Kaplan plot for NR1H4 in