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FLASH GENE
Symbol XBP1 contributors: mct - updated : 06-09-2016
HGNC name X-box binding protein 1
HGNC id 12801
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
  • 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
  • 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
  • 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)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein 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
    SystemTypeDisorderPubmed
    neurologyneurodegenerativealzheimer
    potential of XBP1 as targets for Alzheimer disease therapeutics
    diabetetype 2 
    potential new therapeutic approach for the treatment of type 2 diabetes
    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