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FLASH GENE

Symbol

XBP1

contributors: mct - updated : 06-09-2018

HGNC name	X-box binding protein 1
HGNC id	12801

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

DNA

TYPE	functioning gene
STRUCTURE	6.01 kb     4 Exon(s)

10 Kb 5' upstream gene genomic sequence study

text structure

a cis-acting element in the MDG1/ERdj4 promoter region

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_005080 5 - 1820 NP_005071 29 261 - 2011 21398633 also called XBP1(U), having a hydrophobic region 2 (HR2), which is a membrane-targeting signal, and present only on the XBP1U protein, and a C-terminus responsible for the translational pausing and required for the efficient targeting and splicing of the XBP1u mRNA spliced form acting as a transcription factor and inducing the expression of ER-resident molecular chaperones in the cytosol is an unspliced precursor form of XBP1s, under unstressed conditions upon ER stress, cleaved to initiate the unconventional splicing of XBP1u mRNA on the ER membrane acts as a dominant negative of spliced XBP1 NM_001079539 6 splicing 1810 NP_001073007 56 376 - 2011 21398633 also called XBP1(S) key factor in ER stress, through transcriptionnal regulation of an array of genes, including molecular chaperones upon endoplasmic reticulum (ER) stress, mammalian cells induce the synthesis of a transcriptional activator XBP1s to alleviate the stress phosphate was incorporated into XBP1s mRNA in the cytosol to ligate the two exons active/spliced form of XBP1 protein, that directly binds to the AABS (A-activator-binding site) in the iNOS promoter induces autophagic response in endothelial cells

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 Endocrine placenta       highly Reproductive female system breast mammary gland   highly   female system uterus     highly   female system placenta     highly

cell lineage
cell lines	highly in hepatocellular carcinomas
fluid/secretion

at STAGE

physiological period

pregnancy

Text

placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains

basic leucine zipper (bZIP) motif

HOMOLOGY

interspecies

homolog to murine Xbp1

Homologene

FAMILY	CREB/ATF family
	bZIP family

CATEGORY

immunity/defense , DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,endoplasmic reticulum
	intracellular,nucleus
text	spliced XBP1 translocates into the nucleus and binds as homodimer or heterodimer to the BECN1 gene promoter, leading to BECN1 transcription

basic FUNCTION	acting as an essential survival factor for hypoxic stress and tumor growth
	key transcription factor in the endoplasmic reticulum (ER) stress response pathway
	plays an important role in membrane lipid synthesis in the ER
	transcription factor governing hepatic lipogenesis
	key regulator of the unfolded protein response, required for the unrelated function of normal fatty acid synthesis in the liver
	under endoplasmic reticulum (ER) stress conditions, is processed by unconventional splicing and translated into a functional transcription factor
	required for development and maintenance of secretory cells and linked to JNK activation
	transcription factor essential for hepatocyte growth, as well as for plasma cell differentiation
	key effector of the unfolded protein response (UPR), in skeletal muscle and secretory cells
	regulates functionally distinct targets through different sequence motifs
	may regulate signal transduction, transcription factors and bone marrow colonization in B cells
	major endoplasmic reticulum stress-linked transcriptional factor, contributing to cellular resistance to oxidative stress
	having a protective role against oxidative stress, and its positive regulation of catalase expression may at least in part account for this function
	essential for survival under hypoxic conditions, and positively regulates tumor growth
	key UPR transcription factor that regulates genes involved in protein folding and quality control
	having a function in the control of autophagy and indicate critical cross-talk between these two signaling pathways that can provide protection against neurodegeneration
	key modulator of the UPR (unfolded protein response), which is involved in a wide range of pathological and physiological processes
	involved in the regulation of NOS2 induction by the interaction between its spliced and unspliced forms in response to ER stress
	first identified as a key regulator of major histocompatibility complex (MHC) class II gene expression in B cells
	critical for cell fate determination in response to ER stress
	role for XBP1 in an antiviral response
	the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells
	involvement of XBP1 in huntington pathogenesis probably due to an ER stress-independent mechanism involving the control of FOXO1 and autophagy levels
	unexpected role of XBP1 in controlling a dynamic crosstalk with the FOXO1 and the autophagy pathway to modulate HD pathogenesis
	acetylation status of the ER is regulated by ERN1/XBP1, which acts by controlling the influx of acetyl-CoA through the membrane transporter SLC33A1
	could be used as an important pharmacological target that can regulate the autophagic machinery and endothelial cell death
	may control the transcriptional activation of BECN1 through recruiting other co-factors that induce acetylation and protein stability and/or inhibit deacetylation in a cell-dependent manner
	XBP1 represents a key component of the endoplasmatic reticulum (ER) stress response and is required for the production of several pro-inflammatory cytokines

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

ERN1-XBP1 pathway is involved in osteoblast differentiation through promoting SP7 transcription

a component

key component of the endoplasmic reticulum (ER) stress response

INTERACTION

DNA	binding to HLA-DRA, HLA-DRB promoter

RNA

small molecule

protein	regulating DNAJB9, a member of the DnaJ family (target sequence for the IRE1-XBP1 pathway under ER stress conditions)
	interacting with BHLHA15, a critical regulator of differentiation (important target of XBP1, providing an explanation for developmental defects associated with XBP1 loss of function)
	SUMOylated, mainly by PIAS2 at two lysine residues located in the C-terminal transactivation domain
	target of acetylation and deacetylation mediated by EP300 and SIRT1 (sirtuin 1) respectively (
	interacts with the Forkhead box O1 (FOXO1A) transcription factor and directs it toward proteasome-mediated degradation (through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity)
	IL3 interacting with XBP1 (the proper transcriptional and splicing regulation of XBP1 by IL3 signaling is important in homeostasis of hematopoietic cells)
	ERN1 target XBP1, and are essential for bone morphogenic protein 2-induced osteoblast differentiation
	TMTC3 is involved in the endoplasmic reticulum stress response, by modulating proteasome activity and XBP1 transcript expression
	spliced XBP1 serves as an important effector of ERN1, activating its target genes
	TBC1D23 likely acts downstream of the TLR-signaling adaptors MYD88 and TICAM2 and upstream of the transcription factor XBP1
	ERN1/XBP1 controls the induction of autophagy by activating the expression of the ER membrane transporter SLC33A1, which ensures continuous supply of acetyl-CoA into the lumen of the ER
	BMP2 is known to activate unfolded protein response signaling molecules, including XBP1 and ATF6
	XBP1 associates with RUNX2 and enhances RUNX2-induced chondrocyte hypertrophy
	may be a novel regulator of hypertrophic chondrocyte differentiation by acting as a cofactor of RUNX2 and affecting IHH/PTHRP signaling
	BRD7 regulates XBP1 activity and glucose homeostasis through its interaction with the regulatory subunits of PI3K
	ELL2 is important for many aspects of Ab secretion, XBP1 expression, and the unfolded protein response (UPR) (
	acute METTL14 deficiency in beta-cells induces glucose intolerance by increasing the ERN1/XBP1 pathway
	signaling via TLR7 leads to an upregulation of XBP1 and IFNA1-production
	central role of XBP1 in TLR7-induced IFNA1 production
	among UPR-related transcription factors, XBP1 upregulated ACTN2, whereas XBP1, ATF4 and ATF6 downregulated ACTN3 promoter activity

cell & other

REGULATION

activated by

IRE1

induced by

ATF6

Other	regulated by alpha FP
	activated in B cells when they differentiate to plasma cells

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral       loss of function in prostate cancer in progression tumoral     --over   in primary colorectal carcinomas and in colorectal adenomas constitutional     --over   increased XBP1 expression may contribute to a reduction of oxidative stress and prevention of aging constitutional     --low   led to augmented expression of FOXO1, a key transcription factor regulating autophagy in neurons

Susceptibility

to bipolar disorder to inflammatory bowel disease

Variant & Polymorphism other	C116G increases the risk of bipolar disorder
	variants increasing the risk of inflammatory bowel disease

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed neurology neurodegenerative alzheimer potential of XBP1 as targets for Alzheimer disease therapeutics diabete type 2   potential new therapeutic approach for the treatment of type 2 diabetes immunology autoimmune   is a potential novel therapeutic target in IFNA1-driven autoimmune and inflammatory diseases

ANIMAL & CELL MODELS

	mutant SOD1 transgenic mice with specific deletion of XBP-1 in the nervous system were more resistant to developing disease, correlating with increased levels of autophagy in motoneurons and reduced accumulation of mutant SOD1 aggregates in the spinal cord
	Xbp1-deficient mice were more resistant to developing disease features, associated with improved neuronal survival and motor performance, and a drastic decrease in mHtt levels