XBP1

Summary

XBP1 (X-box binding protein 1, HGNC:12801) is a protein-coding gene on chromosome 22q12.1, encoding X-box-binding protein 1 (P17861). Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR).

This gene encodes a transcription factor that regulates MHC class II genes by binding to a promoter element referred to as an X box. This gene product is a bZIP protein, which was also identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. It may increase expression of viral proteins by acting as the DNA binding partner of a viral transactivator. It has been found that upon accumulation of unfolded proteins in the endoplasmic reticulum (ER), the mRNA of this gene is processed to an active form by an unconventional splicing mechanism that is mediated by the endonuclease inositol-requiring enzyme 1 (IRE1). The resulting loss of 26 nt from the spliced mRNA causes a frame-shift and an isoform XBP1(S), which is the functionally active transcription factor. The isoform encoded by the unspliced mRNA, XBP1(U), is constitutively expressed, and thought to function as a negative feedback regulator of XBP1(S), which shuts off transcription of target genes during the recovery phase of ER stress. A pseudogene of XBP1 has been identified and localized to chromosome 5.

Source: NCBI Gene 7494 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 41 total
• Druggable target: yes — 4 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001079539

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12801
Approved symbol	XBP1
Name	X-box binding protein 1
Location	22q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100219
Ensembl biotype	protein_coding
OMIM	194355
Entrez	7494

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 retained_intron

ENST00000216037, ENST00000344347, ENST00000403532, ENST00000405219, ENST00000482720, ENST00000484256, ENST00000877101, ENST00000933819

RefSeq mRNA: 4 — MANE Select: NM_001079539 NM_001079539, NM_001393999, NM_001394000, NM_005080

CCDS: CCDS13847, CCDS93142

Canonical transcript exons

ENST00000344347 — 6 exons

Exon	Start	End
ENSE00000651986	28799057	28799153
ENSE00001172444	28796047	28796127
ENSE00001382102	28796154	28796192
ENSE00001548174	28800298	28800569
ENSE00001679847	28794560	28795732
ENSE00003052431	28797077	28797205

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 99.66.

FANTOM5 (CAGE): breadth broad, TPM avg 5.0141 / max 307.5890, expressed in 458 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193502	122.5781	1826
193503	76.7350	1822
193501	3.9521	559
193497	3.8547	270
193500	2.3911	245
193496	0.4727	149
193498	0.4700	156
193499	0.2168	110

Top tissues by expression

167 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.66	gold quality
trachea	UBERON:0003126	99.63	gold quality
pancreas	UBERON:0001264	99.59	gold quality
islet of Langerhans	UBERON:0000006	99.51	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.47	gold quality
endometrium epithelium	UBERON:0004811	99.42	gold quality
right lobe of liver	UBERON:0001114	99.22	gold quality
liver	UBERON:0002107	99.18	gold quality
bone marrow cell	CL:0002092	99.06	gold quality
tonsil	UBERON:0002372	99.04	gold quality
rectum	UBERON:0001052	98.98	gold quality
epithelium of bronchus	UBERON:0002031	98.88	gold quality
vermiform appendix	UBERON:0001154	98.85	gold quality
saliva-secreting gland	UBERON:0001044	98.74	gold quality
duodenum	UBERON:0002114	98.74	gold quality
bone element	UBERON:0001474	98.73	gold quality
bone marrow	UBERON:0002371	98.73	gold quality
minor salivary gland	UBERON:0001830	98.65	gold quality
prostate gland	UBERON:0002367	98.65	gold quality
gall bladder	UBERON:0002110	98.60	gold quality
body of stomach	UBERON:0001161	98.50	gold quality
endometrium	UBERON:0001295	98.47	gold quality
lymph node	UBERON:0000029	98.44	gold quality
endocervix	UBERON:0000458	98.37	gold quality
spleen	UBERON:0002106	98.37	gold quality
placenta	UBERON:0001987	98.36	gold quality
stomach	UBERON:0000945	98.35	gold quality
colonic epithelium	UBERON:0000397	98.30	gold quality
left uterine tube	UBERON:0001303	98.28	gold quality
fallopian tube	UBERON:0003889	98.16	gold quality

Single-cell (SCXA)

Detected in 30 experiment(s), a significant marker in 27.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	3111.47
E-MTAB-6653	yes	2525.80
E-MTAB-8530	yes	2132.41
E-HCAD-1	yes	2036.48
E-MTAB-8410	yes	1997.34
E-MTAB-10885	yes	1834.73
E-CURD-122	yes	1803.58
E-MTAB-6386	yes	1691.07
E-CURD-46	yes	1470.37
E-MTAB-9841	yes	1431.15
E-GEOD-139324	yes	1290.16
E-CURD-88	yes	111.18
E-HCAD-4	yes	68.02
E-MTAB-9467	yes	65.91
E-CURD-114	yes	58.36

Regulation

Is transcription factor: yes

JASPAR motifs

Motif	Name	Family
MA0844.1	XBP1	XBP-1-related factors
MA0844.2	XBP1	XBP-1-related factors

JASPAR matrix evidence (PMIDs): PMID:15598891

miRNA regulators (miRDB)

106 targeting XBP1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-3133	99.81	70.92	3506

Literature-anchored findings (GeneRIF, showing 40)

• XBP1 is a key regulator of mammalian ER stress response (PMID:11779464)
• down-regulation of expression correlate with prostate adenocarcinoma progression (PMID:11813207)
• XBP-1 and activation of cAMP response elements expression are upregulated in acquired antiestrogen resistance in breast cancer cells (PMID:12067985)
• XBP1 and ATF6 jointly regulate mammalian ER stress response (PMID:12586069)
• The endoplasmic reticulum stress pathway mediated by ATF6 and by IRE1-XBP1 systems seems essential for the transformation-associated expression of the grp78 gene in hepatocarcinogenesis (PMID:12713871)
• Impaired feedback regulaton of this protein is a genetic risk factor for bipolar disorder. (PMID:12949534)
• XBP-1 is implicated in a gene network that regulates estrogen receptor signaling in breast cancer (PMID:14576841)
• increased expression of the hXBP-1 gene may play some role in human breast carcinogenesis through impairment of cell differentiation regulation (PMID:14634507)
• By subjecting dermal fibroblasts to multiple stresses, strong correlations were found between ATF6 activation and XBP1 splicing, and between GRP78/BiP mRNA and EDEM mRNA accumulation. (PMID:15063770)
• Data suggest that -197C/G in XBP1 is also a genetic risk factor for schizophrenia, and presents a sex-dependent genetic effect for the disorder. (PMID:15184063)
• XBP-1 has a role in ERalpha transcriptional activity through regulation of large-scale chromatin unfolding (PMID:15351732)
• ATF6 and XBP1 have roles in activation of endoplasmic reticulum stress-responsive cis-acting elements (PMID:15598891)
• results reveal a target sequence for the IRE1-XBP1 pathway under ER stress conditions (PMID:15882996)
• Transcriptional regulator XBP-1 governing B-cell terminal cellular differentiation provides multiple myeloma-and other tumor- and nonmalignant-associated cytotoxic T-lymphocyte epitopes. (PMID:16002735)
• The present results suggested that the XBP1 gene polymorphism was associated with the NEO-FFI score of neuroticism in female subjects. (PMID:16154272)
• Describes correlations of XBP1 with IRF1 and NFkB in a tissue microarray study of breast tumors from patients; data analyzed using partial correlation coefficients. (PMID:16327981)
• The functional XBP1 gene polymorphism is not of major importance to schizophrenia in the European populations investigated. (PMID:16342282)
• The swift adapting to physiological changes in the endoplasmic reticulum was studied which required the interplay between XBP1(unspliced) and XBP1 (spliced). (PMID:16461360)
• XBP1 pre-mRNA encodes a negative feed-back regulator of ER stress response (PMID:16461360)
• XBP1 splicing can occur in the cytoplasm, and that cleavage and ligation of XBP1 mRNA during splicing may occur as a coupled reaction. (PMID:17026957)
• Our results clearly establish HBx as an inducer of UPR and the activator of the ATF6 and IRE1-XBP1 pathways of UPR. (PMID:17092596)
• Overexpression of XBP-1 is associated with multiple myeloma pathogenesis (PMID:17418411)
• Misoxidised MHC class I heavy chains activate XBP1 processing in a similar manner to tunicamycin. (PMID:17442311)
• Overexpression of spliced XBP1 prevents cell cycle arrest and antiestrogen-induced cell death through the mitochondrial apoptotic pathway. (PMID:17660348)
• XBP1 and the unfolded protein response modulate responsiveness to estrogens and antiestrogens in breast cancer. (PMID:17660348)
• XBP1 gene promoter can drive its downstream gene expression and its activity is cell line-dependent. (PMID:17884689)
• We report that the plasma cell differentiation factor, XBP-1s, activates the expression of the master regulator of EBV lytic activation, BZLF1. (PMID:17898050)
• When islets were cultured for 24 h at 11.1 mmol/l glucose, there was induction of BiP and XBP-1 in type 2 diabetes islets but not in non-diabetic islets. (PMID:17906960)
• XBP-1s binds to and activates the KSHV immediate-early gene ORF50. (PMID:17928342)
• XBP1 polymorphism (-116C/G) is not involved in susceptibility to suicide. (PMID:17932454)
• Nonalcoholic steatohepatitis is specifically associated with (1) failure to generate sXBP-1 protein and (2) activation of JNK. (PMID:18082745)
• that transcription factors Xbp-1, Blimp-1, and PAX-5-encoded BSAP play important roles in the regulation of plasmacytic differentiation and exert their effects on differentiation induced by low 2ME2 concentrations (PMID:18192112)
• Findings, that XBP-1 isoforms are differently associated with outcome of endocrine therapy for patients, can be explained by higher levels of dominant-negative XBP-1U favouring apoptosis of tumor cells and higher levels of XBP-1S increasing tumor survival (PMID:18386815)
• Xbp1-responsive OS-9 variants in the mammalian endoplasmic reticulum inhibit secretion of misfolded protein conformers and enhancing their disposal (PMID:18417469)
• By chromatin immunoprecipitation and assays using an inducible Spi-B construct BLIMP1 and XBP-1 were identified as direct target genes of Spi-B mediated repression. (PMID:18552212)
• Compared with COPD and donor lungs, protein levels of ER stress mediators, such as ATF-6 and ATF-4 and the apoptosis-inductor CHOP as well as XBP-1, were significantly elevated in lung homogenates and AECIIs of IPF lungs (PMID:18635891)
• An association of XBP1 variants with both forms of human IBD (Crohn’s disease and ulcerative colitis) was identified and replicated (rs35873774; p value 1.6 x 10(-5)) with novel, private hypomorphic variants identified as susceptibility factors. (PMID:18775308)
• Transcriptional induction of the human asparagine synthetase gene during the unfolded protein response does not require the XBP1. (PMID:18840095)
• the -116C/G genotype may be a risk factor for at least pediatric obesity (PMID:18840627)
• Discovered a novel topological feature of signaling in breast cancer cells that links XBP1 to NFkB and BCL2 in response to estrogen and antiestrogen treatment. (PMID:19112081)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	xbp1	ENSDARG00000035622
mus_musculus	Xbp1	ENSMUSG00000020484
rattus_norvegicus	Xbp1	ENSRNOG00000010298

Protein

Protein identifiers

X-box-binding protein 1 — P17861 (reviewed: P17861)

Alternative names: Tax-responsive element-binding protein 5

All UniProt accessions (3): P17861, B1AHH1, B1AHH2

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a transcription factor during endoplasmic reticulum (ER) stress by regulating the unfolded protein response (UPR). Required for cardiac myogenesis and hepatogenesis during embryonic development, and the development of secretory tissues such as exocrine pancreas and salivary gland. Involved in terminal differentiation of B lymphocytes to plasma cells and production of immunoglobulins. Modulates the cellular response to ER stress in a PIK3R-dependent manner. Binds to the cis-acting X box present in the promoter regions of major histocompatibility complex class II genes. Involved in VEGF-induced endothelial cell (EC) proliferation and retinal blood vessel formation during embryonic development but also for angiogenesis in adult tissues under ischemic conditions. Also functions as a major regulator of the UPR in obesity-induced insulin resistance and type 2 diabetes for the management of obesity and diabetes prevention. Plays a role in the unconventional cytoplasmic splicing processing of its own mRNA triggered by the endoplasmic reticulum (ER) transmembrane endoribonuclease ERN1: upon ER stress, the emerging XBP1 polypeptide chain, as part of a mRNA-ribosome-nascent chain (R-RNC) complex, cotranslationally recruits its own unprocessed mRNA through transient docking to the ER membrane and translational pausing, therefore facilitating efficient IRE1-mediated XBP1 mRNA isoform 2 production. In endothelial cells (EC), associated with KDR, promotes IRE1-mediated XBP1 mRNA isoform 2 productions in a vascular endothelial growth factor (VEGF)-dependent manner, leading to EC proliferation and angiogenesis. Functions as a negative feed-back regulator of the potent transcription factor XBP1 isoform 2 protein levels through proteasome-mediated degradation, thus preventing the constitutive activation of the ER stress response signaling pathway. Inhibits the transactivation activity of XBP1 isoform 2 in myeloma cells. Acts as a weak transcriptional factor. Together with HDAC3, contributes to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to EC survival under disturbed flow/oxidative stress. Binds to the ER stress response element (ERSE) upon ER stress. Binds to the consensus 5’-GATGACGTG[TG]N(3)[AT]T-3’ sequence related to cAMP responsive element (CRE)-like sequences. Binds the Tax-responsive element (TRE) present in the long terminal repeat (LTR) of T-cell leukemia virus type 1 (HTLV-I) and to the TPA response elements (TRE). Associates preferentially to the HDAC3 gene promoter region in a static flow-dependent manner. Binds to the CDH5/VE-cadherin gene promoter region. Functions as a stress-inducible potent transcriptional activator during endoplasmic reticulum (ER) stress by inducing unfolded protein response (UPR) target genes via binding to the UPR element (UPRE). Up-regulates target genes encoding ER chaperones and ER-associated degradation (ERAD) components to enhance the capacity of productive folding and degradation mechanism, respectively, in order to maintain the homeostasis of the ER under ER stress. Plays a role in the production of immunoglobulins and interleukin-6 in the presence of stimuli required for plasma cell differentiation. Induces phospholipid biosynthesis and ER expansion. Contributes to the VEGF-induced endothelial cell (EC) growth and proliferation in a Akt/GSK-dependent and/or -independent signaling pathway, respectively, leading to beta-catenin nuclear translocation and E2F2 gene expression. Promotes umbilical vein EC apoptosis and atherosclerotisis development in a caspase-dependent signaling pathway, and contributes to VEGF-induced EC proliferation and angiogenesis in adult tissues under ischemic conditions. Involved in the regulation of endostatin-induced autophagy in EC through BECN1 transcriptional activation. Plays a role as an oncogene by promoting tumor progression: stimulates zinc finger protein SNAI1 transcription to induce epithelial-to-mesenchymal (EMT) transition, cell migration and invasion of breast cancer cells. Involved in adipocyte differentiation by regulating lipogenic gene expression during lactation. Plays a role in the survival of both dopaminergic neurons of the substantia nigra pars compacta (SNpc), by maintaining protein homeostasis and of myeloma cells. Increases insulin sensitivity in the liver as a response to a high carbohydrate diet, resulting in improved glucose tolerance. Also improves glucose homeostasis in an ER stress- and/or insulin-independent manner through both binding and proteasome-induced degradation of the transcription factor FOXO1, hence resulting in suppression of gluconeogenic genes expression and in a reduction of blood glucose levels. Controls the induction of de novo fatty acid synthesis in hepatocytes by regulating the expression of a subset of lipogenic genes in an ER stress- and UPR-independent manner. Associates preferentially to the HDAC3 gene promoter region in a disturbed flow-dependent manner. Binds to the BECN1 gene promoter region. Binds to the CDH5/VE-cadherin gene promoter region. Binds to the ER stress response element (ERSE) upon ER stress. Binds to the 5’-CCACG-3’ motif in the PPARG promoter. Binds to the HEPN1 gene promoter region and activates transcription.

Subunit / interactions. Interacts with HM13. Interacts with RNF139; the interaction induces ubiquitination and degradation of isoform 1. Interacts (via luminal domain) with DERL1; the interaction obviates the need for ectodomain shedding prior to HM13/SPP-mediated XBP1 isoform 1 cleavage. Interacts with isoform 2; the interaction sequesters isoform 2 from the nucleus and enhances isoform 2 degradation in the cytoplasm. Interacts with HDAC3 and AKT1; the interactions occur in endothelial cells (EC) under disturbed flow. Interacts with the oncoprotein FOS. Interacts with SIRT1. Interacts with PIK3R1 and PIK3R2; the interactions are direct and induce translocation of XBP1 isoform 2 into the nucleus and the unfolded protein response (UPR) XBP1-dependent target gene activation in a ER stress- and/or insulin-dependent but PI3K-independent manner. Interacts with FOXO1; the interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway in hepatocytes. Interacts with isoform 1; the interaction sequesters isoform 2 from the nucleus and enhances isoform 2 degradation in the cytoplasm. Interacts with ATF6; the interaction occurs in a ER stress-dependent manner and is required for DNA binding to the unfolded protein response element (UPRE).

Subcellular location. Endoplasmic reticulum Nucleus. Cytoplasm. Endoplasmic reticulum membrane. Membrane Nucleus. Cytoplasm Cytoplasm. Nucleus.

Tissue specificity. Expressed in plasma cells in rheumatoid synovium. Over-expressed in primary breast cancer and metastatic breast cancer cells. Isoform 1 and isoform 2 are expressed at higher level in proliferating as compared to confluent quiescent endothelial cells.

Post-translational modifications. Acetylated by EP300; acetylation positively regulates the transcriptional activity of XBP1 isoform 2. Isoform 2 is deacetylated by SIRT1; deacetylation negatively regulates the transcriptional activity of XBP1 isoform 2. Ubiquitinated, leading to proteasome-mediated degradation in response to ER stress. X-box-binding protein 1, cytoplasmic form and luminal form are produced by intramembrane proteolytic cleavage of ER membrane-anchored isoform 1 triggered by HM13/SPP in a DERL1-RNF139-dependent and VCP/p97-independent manner. X-box-binding protein 1, luminal form is ubiquitinated leading to proteasomal degradation.

Disease relevance. Major affective disorder 7 (MAFD7) [MIM:612371] A major psychiatric disorder that is characterized by severe mood swings, with fluctuation between two abnormal mood states (manic or major depressive episode). Mania is accompanied by symptoms of euphoria, irritability, or excitation, whereas depression is associated with low mood and decreased motivation and energy. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Domain organisation. Isoform 1 and isoform 2 N-terminus domains are necessary for nuclear localization targeting. Isoform 1 C-terminus domain confers localization to the cytoplasm and is sufficient to impose rapid degradation. Isoform 1 transmembrane signal-anchor domain is necessary for its own mRNA to be recruited to the endoplasmic reticulum (ER) which will undergo unconventional ERN1-dependent splicing in response to ER stress. Isoform 1 N-terminus and C-terminus regions are necessary for DNA-binding and weak transcriptional activity, respectively. Isoform 2 N-terminus and C-terminus regions are necessary for DNA-binding and strong transcriptional activity upon ER stress, respectively. Isoform 2 C-terminus region contains a nuclear exclusion signal (NES) at positions 186 through 208. Isoform 2 C-terminus region contains a degradation domain at positions 209 through 261.

Induction. Down-regulated by the B-cell-specific transcription factor PAX5. Up-regulated by interleukin IL-6 in myeloma cells. Up-regulated during plasma-cell differentiation, either through the CD40 receptor signaling pathway or mitogens such as lipopolysaccharide (LPS). Up-regulated at the recovery phase of the endoplasmic reticulum (ER) stress response. Down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (at protein level). Up-regulated early during the ER stress response and gradually decreased at later phase of ER stress. Down-regulated by laminar flow but up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (at protein level). Up-regulated early during the ER stress response in a ATF6-dependent manner. Up-regulated by endostatin in a ERN1-dependent manner. Transiently up-regulated by the mitogenic vascular endothelial growth factor (VEGF) in endothelial cells. Up-regulated by reactive oxygen species.

Miscellaneous. Potent transcriptional activator. Induced by unconventional ERN1-dependent splicing in response to endoplasmic reticulum stress. ERN1 cleaves a 26-bp fragment causing a frameshift of the mRNA transcript.

Similarity. Belongs to the bZIP family.

Isoforms (2)

UniProt ID	Names	Canonical?
P17861-1	1, Unprocessed XBP-1, XBP-1U, XBP1u	yes
P17861-2	2, Processed XBP-1, XBP-1S, XBP1s

RefSeq proteins (4): NP_001073007, NP_001380928, NP_001380929, NP_005071 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004827	bZIP	Domain
IPR046347	bZIP_sf	Homologous_superfamily
IPR052470	ER_Stress-Reg_TF	Family

Pfam: PF07716

UniProt features (37 total): mutagenesis site 16, region of interest 5, chain 3, sequence conflict 3, modified residue 2, sequence variant 2, topological domain 2, site 1, splice variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9NDP	ELECTRON MICROSCOPY	2.82
6R5Q	ELECTRON MICROSCOPY	3
6R6P	ELECTRON MICROSCOPY	3.1
6R6G	ELECTRON MICROSCOPY	3.7
6R7Q	ELECTRON MICROSCOPY	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17861-F1	69.99	0.33

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 194–195 (cleavage; by hm13/spp)

Post-translational modifications (2): 47, 68

Mutagenesis-validated functional residues (16):

Position	Phenotype
189	reduces endoplasmic reticulum localization of its own mrna; when associated with e-193 and d-196.
193	reduces endoplasmic reticulum localization of its own mrna; when associated with e-189 and d-196.
194	reduces endoplasmic reticulum localization of its own mrna; when associated with d-198 and e-205.
196	reduces endoplasmic reticulum localization of its own mrna; when associated with e-189 and e-193.
197	inhibits hm13/spp-mediated degradation of xbp1; when associated with l-199; l-200 and l-203.
198	reduces endoplasmic reticulum localization of its own mrna; when associated with e-194 and e-205.
199	inhibits hm13/spp-mediated degradation of xbp1; when associated with l-197; l-200 and l-203.
200	inhibits hm13/spp-mediated degradation of xbp1; when associated with l-197; l-199 and l-203.
203	inhibits hm13/spp-mediated degradation of xbp1; when associated with l-197; l-199 and l-200.
205	reduces endoplasmic reticulum localization of its own mrna; when associated with e-194 and d-198.
212	does not induce glycosylation.
215	induces glycosylation.
232	induces glycosylation.
246	reduces translational pausing, membrane targeting and cytoplasmic splicing of its own mrna.
255	increases translational pausing of its own mrna.
256	reduces translational pausing, membrane targeting and cytoplasmic splicing of its own mrna.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes
R-HSA-381070	IRE1alpha activates chaperones
R-HSA-381183	ATF6 (ATF6-alpha) activates chaperone genes

MSigDB gene sets: 701 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_HEPATOCYTE_PROLIFERATION, GOBP_ACYLGLYCEROL_HOMEOSTASIS, AGGAAGC_MIR5163P, MYAATNNNNNNNGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, BERENJENO_ROCK_SIGNALING_NOT_VIA_RHOA_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS

GO Biological Process (90): negative regulation of transcription by RNA polymerase II (GO:0000122), angiogenesis (GO:0001525), regulation of cell growth (GO:0001558), liver development (GO:0001889), positive regulation of protein phosphorylation (GO:0001934), endothelial cell proliferation (GO:0001935), glandular epithelial cell maturation (GO:0002071), positive regulation of immunoglobulin production (GO:0002639), regulation of transcription by RNA polymerase II (GO:0006357), transcription by RNA polymerase II (GO:0006366), ubiquitin-dependent protein catabolic process (GO:0006511), fatty acid biosynthetic process (GO:0006633), autophagy (GO:0006914), immune response (GO:0006955), muscle organ development (GO:0007517), positive regulation of cell population proliferation (GO:0008284), regulation of autophagy (GO:0010506), positive regulation of autophagy (GO:0010508), negative regulation of myotube differentiation (GO:0010832), protein transport (GO:0015031), negative regulation of translation (GO:0017148), positive regulation of cell migration (GO:0030335), negative regulation of transforming growth factor beta receptor signaling pathway (GO:0030512), endoplasmic reticulum unfolded protein response (GO:0030968), exocrine pancreas development (GO:0031017), regulation of protein stability (GO:0031647), protein destabilization (GO:0031648), cellular response to nutrient (GO:0031670), positive regulation of TOR signaling (GO:0032008), positive regulation of interleukin-6 production (GO:0032755), cellular response to insulin stimulus (GO:0032869), cellular response to oxidative stress (GO:0034599), response to endoplasmic reticulum stress (GO:0034976), intracellular triglyceride homeostasis (GO:0035356), positive regulation of vascular wound healing (GO:0035470), cellular response to vascular endothelial growth factor stimulus (GO:0035924), IRE1-mediated unfolded protein response (GO:0036498), ATF6-mediated unfolded protein response (GO:0036500), ERAD pathway (GO:0036503), cellular response to glucose starvation (GO:0042149)

GO Molecular Function (19): transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), cis-regulatory region sequence-specific DNA binding (GO:0000987), protease binding (GO:0002020), DNA-binding transcription factor activity (GO:0003700), protein kinase binding (GO:0019901), nuclear estrogen receptor binding (GO:0030331), chromatin DNA binding (GO:0031490), ubiquitin protein ligase binding (GO:0031625), identical protein binding (GO:0042802), histone deacetylase binding (GO:0042826), ubiquitin-like protein ligase binding (GO:0044389), protein heterodimerization activity (GO:0046982), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), RNA polymerase II transcription regulator complex (GO:0090575), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
IRE1alpha activates chaperones	1
Unfolded Protein Response (UPR)	1
ATF6 (ATF6-alpha) activates chaperones	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription cis-regulatory region binding	3
enzyme binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
autophagy	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
DNA binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
gland development	1
hepaticobiliary system development	1
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
epithelial cell proliferation	1
glandular epithelial cell development	1
columnar/cuboidal epithelial cell maturation	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
DNA-templated transcription	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
immune system process	1
response to stimulus	1

Protein interactions and networks

STRING

3790 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XBP1	ATF6	P18850	990
XBP1	HIF1A	Q16665	985
XBP1	ERN1	O75460	976
XBP1	HSPA5	P11021	964
XBP1	PIK3R2	O00459	936
XBP1	EDEM1	Q92611	907
XBP1	ATF4	P18848	892
XBP1	EIF2AK3	Q9NZJ5	892
XBP1	FOXO1	Q12778	890
XBP1	DDIT3	P35638	886
XBP1	EIF2S1	P05198	860
XBP1	ERN2	Q76MJ5	860
XBP1	PRDM1	O75626	858
XBP1	ATF6B	Q99941	853
XBP1	EIF2AK2	P19525	844

IntAct

36 interactions, top by confidence:

A	B	Type	Score
XBP1	XBP1	psi-mi:“MI:0407”(direct interaction)	0.730
ATF6	XBP1	psi-mi:“MI:0407”(direct interaction)	0.620
CREBZF	XBP1	psi-mi:“MI:0407”(direct interaction)	0.620
XBP1	ATF6	psi-mi:“MI:0407”(direct interaction)	0.620
XBP1	CREBZF	psi-mi:“MI:0407”(direct interaction)	0.620
HIF1A	XBP1	psi-mi:“MI:0915”(physical association)	0.590
XBP1	UBE2V1	psi-mi:“MI:0915”(physical association)	0.560
ATF6B	XBP1	psi-mi:“MI:0407”(direct interaction)	0.440
XBP1	ATF6B	psi-mi:“MI:0407”(direct interaction)	0.440
XBP1	ZNF440	psi-mi:“MI:0915”(physical association)	0.370
XBP1	ZNF580	psi-mi:“MI:0915”(physical association)	0.370
GLI1	XBP1	psi-mi:“MI:0915”(physical association)	0.370
H1-0	XBP1	psi-mi:“MI:0915”(physical association)	0.370
HDGF	XBP1	psi-mi:“MI:0915”(physical association)	0.370
RBL2	XBP1	psi-mi:“MI:0915”(physical association)	0.370
SRSF1	XBP1	psi-mi:“MI:0915”(physical association)	0.370
SSX4	XBP1	psi-mi:“MI:0915”(physical association)	0.370
XBP1	PCBD2	psi-mi:“MI:0915”(physical association)	0.370
XBP1	NR0B2	psi-mi:“MI:0915”(physical association)	0.370
XBP1	FUBP3	psi-mi:“MI:0915”(physical association)	0.370
XBP1	H1-10	psi-mi:“MI:0915”(physical association)	0.370
XBP1	TRIP4	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (64): XBP1 (Affinity Capture-Western), HM13 (Affinity Capture-Western), XBP1 (Affinity Capture-Western), UBE2I (Two-hybrid), XBP1 (Two-hybrid), XBP1 (Affinity Capture-Western), KAT2B (Affinity Capture-Western), KAT2A (Affinity Capture-Western), XBP1 (Affinity Capture-Western), XBP1 (Affinity Capture-MS), XBP1 (Affinity Capture-MS), XBP1 (Affinity Capture-MS), XBP1 (Two-hybrid), XBP1 (Affinity Capture-Western), MDM2 (Affinity Capture-Western)

ESM2 similar proteins: A0A5F9ZHS7, B1ASB6, C9JSJ3, I7HJS4, O08686, O35426, O60393, O88286, P17861, P20428, P31357, Q05AH6, Q15583, Q1WG82, Q2M1V0, Q2MHN3, Q2YDG1, Q32LE6, Q3SZZ2, Q3TQ03, Q495C1, Q497K7, Q4R2Z8, Q5HZG9, Q5IS58, Q6ZN32, Q7Z572, Q80W88, Q8BHP2, Q8CGW9, Q8IX15, Q8IXT2, Q8IY92, Q8IZ20, Q8K3E9, Q8N1L9, Q8N365, Q8N7G0, Q8R1H8, Q96MN9

Diamond homologs: G5EE07, O35426, P17861, Q3SZZ2, Q9R1S4, O24646, Q8W191, Q9SM50

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
BACH2	“down-regulates quantity by repression”	XBP1	“transcriptional regulation”
XBP1	“up-regulates quantity by expression”	NPPB	“transcriptional regulation”
XBP1	“up-regulates activity”	B-Lymphocyte_diff
ERK1/2	“down-regulates quantity by destabilization”	XBP1	phosphorylation
ERN1	“up-regulates activity”	XBP1	phosphorylation
XBP1	“up-regulates activity”	XBP1	binding
PSMA6	“down-regulates quantity by destabilization”	XBP1	binding
PSMA7	“down-regulates quantity by destabilization”	XBP1	binding
PSMA5	“down-regulates quantity by destabilization”	XBP1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

41 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	21
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

545 predictions. Top by Δscore:

Variant	Effect	Δscore
22:28795728:TCAGA:T	acceptor_gain	1.0000
22:28795729:CAGA:C	acceptor_gain	1.0000
22:28795729:CAGAC:C	acceptor_gain	1.0000
22:28795730:AGA:A	acceptor_gain	1.0000
22:28795730:AGAC:A	acceptor_loss	1.0000
22:28795731:GA:G	acceptor_gain	1.0000
22:28795732:AC:A	acceptor_loss	1.0000
22:28795733:C:CC	acceptor_gain	1.0000
22:28795743:C:CT	acceptor_gain	1.0000
22:28795744:A:T	acceptor_gain	1.0000
22:28796042:CCTAC:C	donor_loss	1.0000
22:28796043:CTACC:C	donor_loss	1.0000
22:28796044:TAC:T	donor_loss	1.0000
22:28796045:A:AC	donor_gain	1.0000
22:28796045:A:T	donor_loss	1.0000
22:28796046:C:CC	donor_gain	1.0000
22:28796046:C:CG	donor_loss	1.0000
22:28796046:CCT:C	donor_gain	1.0000
22:28796188:TTCCC:T	acceptor_gain	1.0000
22:28796189:TCCC:T	acceptor_gain	1.0000
22:28796190:CCC:C	acceptor_gain	1.0000
22:28796190:CCCC:C	acceptor_gain	1.0000
22:28796191:CC:C	acceptor_gain	1.0000
22:28796191:CCC:C	acceptor_gain	1.0000
22:28796192:CC:C	acceptor_gain	1.0000
22:28796192:CCTGG:C	acceptor_loss	1.0000
22:28796193:C:CC	acceptor_gain	1.0000
22:28796193:C:T	acceptor_gain	1.0000
22:28796193:CTGG:C	acceptor_loss	1.0000
22:28796194:T:C	acceptor_loss	1.0000

AlphaMissense

2413 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:28799138:T:A	R81S	1.000
22:28799138:T:G	R81S	1.000
22:28799088:A:G	L98P	0.999
22:28799108:C:A	K91N	0.999
22:28799108:C:G	K91N	0.999
22:28799112:C:G	R90P	0.999
22:28799121:G:T	A87D	0.999
22:28799126:C:A	Q85H	0.999
22:28799126:C:G	Q85H	0.999
22:28799130:G:T	A84D	0.999
22:28799140:T:C	R81G	0.999
22:28799141:G:C	N80K	0.999
22:28799141:G:T	N80K	0.999
22:28799142:T:C	N80S	0.999
22:28799143:T:C	N80D	0.999
22:28799144:T:A	K79N	0.999
22:28799144:T:G	K79N	0.999
22:28799146:T:C	K79E	0.999
22:28799148:A:G	L78P	0.999
22:28799153:C:A	R76S	0.999
22:28799153:C:G	R76S	0.999
22:28800298:C:A	R76M	0.999
22:28800298:C:G	R76T	0.999
22:28800301:C:A	R75M	0.999
22:28797195:A:G	L112P	0.998
22:28799104:C:G	A93P	0.998
22:28799117:T:A	R88S	0.998
22:28799117:T:G	R88S	0.998
22:28799118:C:A	R88I	0.998
22:28799118:C:G	R88T	0.998

dbSNP variants (sampled 300 via entrez): RS1000214303 (22:28797455 C>T), RS1000599196 (22:28798416 C>T), RS1001006132 (22:28798113 C>G), RS1001048447 (22:28801571 A>G), RS1001109797 (22:28801893 G>A), RS1001462729 (22:28799225 C>T), RS1001799593 (22:28797693 GAAT>G), RS1001915918 (22:28797407 A>G), RS1003149750 (22:28801672 C>T), RS1003514456 (22:28800121 C>A,T), RS1003627507 (22:28802079 G>A), RS1004219892 (22:28799804 C>G,T), RS1004370332 (22:28800327 G>A,C), RS1004701458 (22:28798699 T>A,C), RS1004743904 (22:28800091 G>A)

Disease associations

OMIM: gene MIM:194355 | disease phenotypes: MIM:612371

GenCC curated gene-disease

Mondo (1): major affective disorder 7 (MONDO:0012881)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001674_3	Esophageal cancer (squamous cell)	4.000000e-15
GCST002553_2	Pancreatic cancer	1.000000e-08
GCST002568_9	Esophageal squamous cell carcinoma	4.000000e-07
GCST006010_20	Mean arterial pressure	3.000000e-08
GCST006288_693	Heel bone mineral density	7.000000e-09
GCST010083_280	Hemoglobin levels	3.000000e-19
GCST90011900_17	Serum alkaline phosphatase levels	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006340	mean arterial pressure
EFO:0009270	heel bone mineral density
EFO:0004509	hemoglobin measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567529	Major Affective Disorder 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1741176 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

4 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 71,475 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL17157	TERFENADINE	4	25,393
CHEMBL421701	DITHIAZANINE IODIDE	4	3,372
CHEMBL46516	FLUSPIRILENE	4	41,239
CHEMBL1256686	CALCIMYCIN	2	1,471

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2269577	Efficacy,Toxicity	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2269577	XBP1, ZNRF3	3	2.00	1	Platinum compounds

Binding affinities (BindingDB)

192 measured of 229 human assays (940 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
7-[(E)-but-2-enyl]-3-methyl-8-(3-phenylpropylsulfanyl)purine-2,6-dione	EC50	0.00868 nM
(E)-4-(2-sulfanylidene-1,3-benzoxazol-3-yl)-3-buten-2-one	EC50	10 nM
4-[2,4-bis(chloranyl)phenoxy]-N-(cyclohexylmethylideneamino)butanamide	IC50	24.4 nM
2-[[2-[(6-methyl-1,3-benzothiazol-2-yl)amino]-2-oxoethyl]thio]acetic acid [2-(4-bromophenyl)-2-oxoethyl] ester	IC50	39.3 nM
MLS000558139	EC50	45.4 nM
3-[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]propanamide	IC50	47.9 nM
cid_3396	KI	56 nM
3-(7-methyl-2-imidazo[1,2-a]pyridinyl)-1-benzopyran-2-one	EC50	137 nM
2-({[2-(4-ethoxyphenyl)-5-methyl-1,3-oxazol-4-yl]methyl}thio)-N-(2-furylmethyl)acetamide	IC50	140 nM
4-methyl-N-(3-quinolinyl)benzamide	EC50	200 nM
2-[4-[(5-tert-butyl-2-furoyl)amino]phenyl]acetic acid	EC50	230 nM
3-[(2-chloro-4-methylol-phenoxy)methyl]benzoic acid	IC50	288 nM
2-(1-propyl-4-pyridinylidene)indene-1,3-dione	IC50	296 nM
1,4-diketo-3-(4-methoxyphenyl)naphthalene-2-carboxylic acid ethyl ester	IC50	322 nM
MLS000374486	IC50	348 nM
3-[(4-methoxyphenoxy)methyl]benzoic acid	IC50	370 nM
(3Z,5E)-1-ethyl-3,5-bis(3-hydroxy-4-methoxy-benzylidene)-4-piperidone	EC50	380 nM
(Z)-2,3-bis(chloranyl)-3-[(4-chlorophenyl)methylsulfinyl]-N-(6-methoxypyridin-3-yl)prop-2-enamide	EC50	460 nM
3-[(2-chloranylphenoxy)methyl]benzoic acid	IC50	538 nM
MLS000566821	EC50	550 nM
(3aS,5R,5aR,8aS,9aR)-5,8a-dimethyl-1-methylene-3a,4,5,5a,9,9a-hexahydroazuleno[6,7-b]furan-2,8-dione	EC50	590 nM
2-methylbenzo-1,4-quinone 4-[O-(3,4,5-trimethoxybenzoyl)oxime]	IC50	623 nM
(NZ)-N-[3-(4-hydroxyanilino)-4-keto-1-naphthylidene]thiophene-2-sulfonamide	IC50	656 nM
(5-chloro-2-pyridyl)-[4-(2-thienyl)thiazol-2-yl]amine	EC50	686 nM
5-(4-hydroxyphenyl)-N-[2-(trifluoromethyl)phenyl]isoxazole-3-carboxamide	EC50	778 nM
2-[(2,4-dimethoxyanilino)methylene]indane-1,3-quinone	EC50	790 nM
2-[2-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)-2-keto-ethyl]-1,1-diketo-1,2-benzothiazol-3-one	IC50	816 nM
2-[(E)-2-(3-methylphenyl)ethenyl]-1H-quinazolin-4-one	EC50	829 nM
5-(4-methylphenyl)-3-(2-pyridinyl)-1,2,4-oxadiazole	IC50	1000 nM
1-cyclohexyl-3-[2-(cyclohexylcarbamoylamino)phenyl]urea	IC50	1100 nM
1-(3-chlorophenyl)-3-(2-pyridin-3-ylpyrimidin-4-yl)urea	EC50	1110 nM
(3aR,5R,5aR,8aR,9S,9aS)-5,8a-dimethyl-1-methylidene-9-oxidanyl-3a,4,5,5a,9,9a-hexahydroazuleno[6,7-b]furan-2,8-dione	EC50	1110 nM
(4,6-difluoro-1,3-benzothiazol-2-yl)-([1,3]dioxolo[4,5-f][1,3]benzothiazol-6-yl)amine	IC50	1120 nM
(E)-3-(3,4-dimethoxyphenyl)-1-(2-ethylsulfanylbenzimidazol-1-yl)prop-2-en-1-one	EC50	1130 nM
(E)-1-(2-prop-2-enylsulfanylbenzimidazol-1-yl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one	EC50	1160 nM
2-(1-ethyl-4-pyridinylidene)indene-1,3-dione	IC50	1200 nM
(2E)-2-(1-cyano-2,2,2-trifluoro-ethylidene)-5-phenyl-1,3-oxathiole-4-carboxylic acid ethyl ester	EC50	1270 nM
5’-isopropyl-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3’-indoline]-2’-one	EC50	1420 nM
3-amino-N-(5-methyl-1,3,4-thiadiazol-2-yl)-6-(2-thienyl)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-carboxamide	IC50	1570 nM
(E)-1-(1-benzimidazolyl)-3-(3-nitrophenyl)-2-propen-1-one	EC50	1680 nM
MLS000533118	EC50	1730 nM
(1Z,3Z)-1,4-bis(butylsulfonyl)buta-1,3-diene	IC50	1780 nM
5-[(E)-3-(5-Nitro-furan-2-yl)-prop-2-en-(Z)-ylidene]-2-thioxo-thiazolidin-4-one	IC50	1920 nM
2-chloranyl-1-[(5Z)-5-[[2-(4-nitrophenyl)hydrazinyl]methylidene]pyrrol-3-yl]ethanone	EC50	1940 nM
2-[(1,1-dioxido-1-benzothien-3-yl)thio]-1,3-benzothiazole	IC50	1950 nM
MLS000083777	IC50	1950 nM
3-phenyl-9,10-phenanthrenedione	IC50	2000 nM
MLS000729575	EC50	2000 nM
3-(4-Carboxy-benzyl)-4-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-phenylamino-thiazol-3-ium	IC50	2010 nM
(3-benzoxyphenyl)-(5-phenyl-1,3,4-oxadiazol-2-yl)methanol	EC50	2080 nM

ChEMBL bioactivities

583 potent at pChembl≥5 of 584 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.65	EC50	2.25	nM	CHEMBL3331117
6.80	IC50	160	nM	CHEMBL1507250
6.80	IC50	160	nM	CHEMBL1578584
6.80	IC50	160	nM	CHEMBL1405952
6.80	IC50	160	nM	CHEMBL1329798
6.80	IC50	160	nM	CHEMBL1452159
6.80	IC50	160	nM	CHEMBL300389
6.80	IC50	160	nM	CHEMBL1582448
6.80	IC50	160	nM	CHEMBL1524484
6.80	IC50	160	nM	CHEMBL1521960
6.80	IC50	160	nM	CHEMBL1884996
6.80	IC50	160	nM	CHEMBL1544818
6.80	IC50	160	nM	CHEMBL1900850
6.80	IC50	160	nM	ANGUIDIN
6.80	IC50	160	nM	CHEMBL1409900
6.80	IC50	160	nM	CHEMBL3185655
6.80	IC50	160	nM	CHEMBL3195389
6.80	IC50	160	nM	CHEMBL1523019
6.80	IC50	160	nM	CHEMBL1573994
6.80	IC50	160	nM	CHEMBL1453996
6.80	IC50	160	nM	CHEMBL1312928
6.80	IC50	160	nM	CHEMBL1577639
6.80	IC50	160	nM	CHEMBL1518905
6.68	EC50	210	nM	CHEMBL3614048
6.66	EC50	220	nM	CHEMBL3614047
6.54	IC50	290	nM	CHEMBL1389966
6.52	IC50	300	nM	CHEMBL1310617
6.48	IC50	330	nM	CHEMBL1607086
6.43	IC50	370	nM	CHEMBL1562575
6.41	IC50	390	nM	CHEMBL1349625
6.27	IC50	540	nM	CHEMBL1990598
6.26	IC50	550	nM	CHEMBL3192555
6.26	IC50	550	nM	CHEMBL1541339
6.25	IC50	560	nM	CHEMBL1985061
6.18	IC50	660	nM	CHEMBL1537489
6.13	IC50	740	nM	CHEMBL1511363
6.06	IC50	870	nM	CHEMBL1458548
6.04	IC50	910	nM	CHEMBL1570216
6.04	IC50	920	nM	CHEMBL1382438
6.03	IC50	940	nM	CHEMBL1459140
6.01	IC50	980	nM	CHEMBL1465592
6.01	IC50	980	nM	CHEMBL1547559
6.00	IC50	990	nM	CHEMBL1567571
6.00	IC50	1000	nM	CHEMBL1454183
5.99	IC50	1030	nM	CHEMBL1569585
5.93	IC50	1170	nM	CHEMBL2095095
5.92	IC50	1200	nM	CHEMBL1600073
5.92	IC50	1210	nM	CHEMBL2000517
5.90	IC50	1270	nM	CHEMBL1588525
5.90	IC50	1260	nM	CHEMBL1460889

PubChem BioAssay actives

3 with measured affinity, of 72 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
5,7,17,19-tetraoxa-13-azahexacyclo[11.11.0.02,10.04,8.015,23.016,20]tetracosa-1(24),2,4(8),9,15(23),16(20),21-heptaene	1245295: Transactivation of XBP1 (unknown origin) transfected in rat IEC-6 cells after 48 hrs by dual luciferase reporter gene assay	ec50	0.0022	uM
3-(24-methyl-5,7,17,19-tetraoxa-13-azoniahexacyclo[11.11.0.02,10.04,8.015,23.016,20]tetracosa-1(13),2,4(8),9,14,16(20),21,23-octaen-14-yl)but-3-en-2-one chloride	1245295: Transactivation of XBP1 (unknown origin) transfected in rat IEC-6 cells after 48 hrs by dual luciferase reporter gene assay	ec50	0.2100	uM
1-(5,7,17,19-tetraoxa-13-azahexacyclo[11.11.0.02,10.04,8.015,23.016,20]tetracosa-1(24),2,4(8),9,15(23),16(20),21-heptaen-14-yl)propan-2-one	1245295: Transactivation of XBP1 (unknown origin) transfected in rat IEC-6 cells after 48 hrs by dual luciferase reporter gene assay	ec50	0.2200	uM

CTD chemical–gene interactions

265 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Thapsigargin	increases splicing, affects splicing, increases activity, increases cleavage, decreases response to substance (+2 more)	25
Tunicamycin	decreases reaction, increases splicing, increases expression	15
4-phenylbutyric acid	decreases reaction, increases expression, increases splicing, decreases expression	8
sodium arsenite	decreases expression, increases expression, increases splicing, affects reaction, increases secretion (+2 more)	7
Estradiol	increases expression, decreases reaction, affects binding, increases reaction	6
Cadmium Chloride	increases acetylation, affects reaction, decreases reaction, increases expression, affects activity (+4 more)	6
Quercetin	decreases reaction, increases splicing, decreases expression, increases expression	5
Nanotubes, Carbon	decreases splicing, increases expression	5
Resveratrol	decreases reaction, increases expression, increases splicing	4
Arsenic Trioxide	increases abundance, increases expression, increases splicing, increases reaction, decreases reaction	4
Acetylcysteine	decreases reaction, increases splicing, increases abundance	4
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation, increases expression	4
Amiodarone	increases expression, increases splicing, decreases expression, decreases reaction	4
Particulate Matter	increases abundance, increases expression, affects cotreatment, affects expression, increases reaction (+1 more)	4
methylmercuric chloride	increases expression	3
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases reaction, decreases response to substance, decreases reaction, increases expression, affects cotreatment (+2 more)	3
STF 083010	decreases reaction, increases expression, affects cotreatment, increases splicing	3
(+)-JQ1 compound	decreases expression, affects binding, decreases reaction, increases reaction, increases expression	3
Benzo(a)pyrene	decreases expression, increases expression	3
Cisplatin	affects activity, affects cotreatment, decreases expression, increases expression	3
Glucosamine	increases splicing, decreases reaction, increases expression, decreases splicing	3
Homocysteine	affects reaction, increases splicing, decreases expression, increases expression	3
Lipopolysaccharides	increases phosphorylation, decreases reaction, increases expression, decreases expression, affects reaction (+3 more)	3
Rotenone	increases splicing, increases expression, increases reaction	3
Tobacco Smoke Pollution	increases expression, increases splicing, decreases reaction, increases reaction, decreases response to substance (+4 more)	3
Tretinoin	decreases reaction, increases expression, decreases expression	3
aristolochic acid I	decreases expression, increases splicing	2
bisphenol A	decreases reaction, increases expression, affects reaction, increases phosphorylation	2
methylselenic acid	increases splicing	2
trichostatin A	affects expression, increases expression	2

ChEMBL screening assays

7 unique, capped per target: 6 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1738682	Functional	PUBCHEM_BIOASSAY: XBP1 DR counterscreen for CHOP. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID2732, AID493217]	PubChem BioAssay data set
CHEMBL3377231	Binding	Induction of XBP1 (unknown origin) expressed in CHOK1 cells by luciferase reporter gene assay	Discovery of Sulfonamidebenzamides as Selective Apoptotic CHOP Pathway Activators of the Unfolded Protein Response. — ACS Med Chem Lett

Cellosaurus cell lines

14 cell lines: 8 cancer cell line, 3 embryonic stem cell, 3 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A7X8	SEES3-1V human XBP1, clone1	Embryonic stem cell	Male
CVCL_A7X9	SEES3-1V human XBP1, clone2	Embryonic stem cell	Male
CVCL_A7Y0	SEES3-1V human XBP1, clone3	Embryonic stem cell	Male
CVCL_C4MA	T47D/XBP1	Cancer cell line	Female
CVCL_D1ZL	Abcam A-549 XBP1 KO	Cancer cell line	Male
CVCL_D2DM	Abcam HCT 116 XBP1 KO	Cancer cell line	Male
CVCL_D2PF	Abcam THP-1 XBP1 KO	Cancer cell line	Male
CVCL_E8IA	CHOS-X	Spontaneously immortalized cell line	Female
CVCL_EQ29	MCF7/XBP1	Cancer cell line	Female
CVCL_GP78	CHO XBP1s	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.