XBP-1 is a bZIP transcription factor that functions as the primary effector of the IRE-1 branch of the endoplasmic reticulum unfolded protein response (UPR-ER). The xbp-1 mRNA undergoes unconventional cytoplasmic splicing by the ER transmembrane endoribonuclease IRE-1 during ER stress, producing the active spliced isoform (XBP-1s) that induces transcription of UPR target genes including hsp-3, hsp-4 (BiP homologs), and other ER chaperones via binding to the UPR element (UPRE). XBP-1 is essential for maintaining ER homeostasis, particularly during physiological demands such as innate immune activation, heat stress, and developmental secretory capacity. XBP-1 functions redundantly with PEK-1 (PERK) and ATF-6 pathways; loss of xbp-1 combined with either pek-1 or atf-6 causes synthetic larval lethality. XBP-1s also functions cell-nonautonomously from neurons to activate UPR in distal tissues, regulate lipid metabolism, and extend lifespan.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: XBP-1 is a bZIP transcription factor that binds to specific DNA sequences including the UPR element (UPRE) to activate transcription of ER stress genes. This annotation is phylogenetically inferred and consistent with the conserved DNA-binding activity of XBP1 family members across species (PMID:11779465). Reason: The IBA annotation is well-supported. XBP-1 contains a conserved bZIP domain (residues 61-117) and functions as a transcriptional activator of UPR genes. The spliced form binds to UPRE sequences in promoters of target genes like hsp-4. This is consistent with direct experimental evidence in PMID:24068940 showing XBP-1 ChIP occupancy at target gene promoters. Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription PMID:24068940 binds to common downstream targets with XBP-1 and ATF-6 file:worm/xbp-1/xbp-1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: XBP-1s is a potent transcriptional activator during ER stress, inducing expression of UPR target genes through binding to UPRE elements. This core molecular function is conserved from yeast to humans (PMID:11779465). Reason: This is a core molecular function of XBP-1. The spliced isoform (XBP-1s) functions as a stress-inducible transcriptional activator, directly binding DNA and inducing transcription of ER stress response genes. Evidence from multiple publications demonstrates that XBP-1 activates transcription of hsp-3, hsp-4, and other UPR genes (PMID:11779465, PMID:16184190). Supporting Evidence: PMID:11779465 The unfolded protein response (UPR) is a transcriptional and translational intracellular signaling pathway PMID:16184190 ire-1 and xbp-1 together regulate transcription of most i-UPR genes |
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: XBP-1, as a bZIP transcription factor, localizes to the nucleus to carry out its transcriptional regulatory function. This is consistent with its role in activating UPR target gene expression. Reason: Nuclear localization is expected and required for XBP-1's function as a transcription factor. UniProt (G5EE07) annotates nuclear localization based on the bZIP domain (PROSITE-ProRule:PRU00978). The IBA annotation is phylogenetically consistent with the conserved nuclear function of XBP1 family members. Supporting Evidence: UniProt:G5EE07 SUBCELLULAR LOCATION: Nucleus |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | ACCEPT | Summary: This IEA annotation derives from UniProtKB keyword mapping. XBP-1 contains a bZIP domain that mediates DNA binding. Reason: The annotation is correct but less specific than the IBA annotation for GO:0000977 (sequence-specific DNA binding). Given that more specific terms are already present, this broader term is acceptable as it captures the fundamental DNA binding capability of the bZIP domain. Supporting Evidence: UniProt:G5EE07 InterPro; IPR004827; bZIP |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation derives from InterPro domain mapping. XBP-1 has the bZIP domain characteristic of transcription factors. Reason: Correct but less specific than GO:0000981. The annotation accurately reflects XBP-1's function as a transcription factor, supported by the bZIP domain (IPR004827) and ER stress-regulated TF family (IPR052470). Supporting Evidence: UniProt:G5EE07 InterPro; IPR004827; bZIP |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Duplicate annotation for nuclear localization, derived from UniProtKB subcellular location mapping. Reason: This is a duplicate of the IBA annotation but from IEA evidence. Nuclear localization is correct for XBP-1 function. Duplicates with different evidence codes are acceptable in GO. Supporting Evidence: UniProt:G5EE07 SUBCELLULAR LOCATION: Nucleus |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: This annotation indicates XBP-1 is involved in transcription. Derived from UniProtKB keyword mapping. Reason: XBP-1 is directly involved in transcription as a transcription factor. The annotation is correct though less informative than the more specific annotations for transcriptional regulation. Supporting Evidence: UniProt:G5EE07 Transcription; Transcription regulation |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: This IEA annotation indicates XBP-1 regulates transcription, derived from InterPro domain mapping. Reason: Correct annotation. XBP-1s is a transcriptional activator that regulates expression of UPR target genes. This is well-established from genetic studies showing XBP-1 is required for induction of hsp-3, hsp-4, and other ER stress genes (PMID:11779465, PMID:16184190). Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:16184190 Genetic interactions due to constitutive and inducible gene ... | ACCEPT | Summary: Shen et al. (2005) demonstrated that XBP-1 is required for induction of UPR target genes. Microarray analysis showed that ire-1 and xbp-1 together regulate transcription of most inducible UPR (i-UPR) genes. Reason: Well-supported by experimental evidence. The paper demonstrates that xbp-1 mutation reduces expression of i-UPR genes, and XBP-1 functions as a transcriptional activator downstream of IRE-1 splicing. This is a core molecular function of XBP-1. Supporting Evidence: PMID:16184190 ire-1 and xbp-1 together regulate transcription of most i-UPR genes PMID:16184190 IRE-1 Acts through XBP-1 to Induce Transcription of Many UPR Genes |
| GO:0036498 IRE1-mediated unfolded protein response | IMP PMID:22125500 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabdi... | ACCEPT | Summary: Richardson et al. (2011) showed that XBP-1 is the essential downstream effector of IRE-1. XBP-1 deficiency causes constitutive ER stress with elevated IRE-1 and PEK-1 activity, demonstrating its central role in the IRE-1-mediated UPR. Reason: This is a core biological process for XBP-1. The paper provides IMP evidence showing that xbp-1 mutants have constitutive activation of the IRE-1 pathway and increased sensitivity to ER stress. XBP-1 is the primary transcriptional effector of the IRE-1 branch. Supporting Evidence: PMID:22125500 in Caenorhabditis elegans XBP-1 deficiency results in constitutive ER stress, reflected by increased basal levels of IRE-1 and PEK-1 activity under physiological conditions PMID:22125500 XBP-1 deficiency results in a dramatic increase in IRE-1 activity |
| GO:0008340 determination of adult lifespan | IMP PMID:23791175 XBP-1 is a cell-nonautonomous regulator of stress resistance... | KEEP AS NON CORE | Summary: Taylor and Dillin (2013) demonstrated that XBP-1s expression, particularly in neurons, extends lifespan through cell-nonautonomous activation of UPR in distal tissues. Reason: Well-supported but represents a pleiotropic/indirect effect rather than core function. XBP-1s overexpression in neurons increases longevity, and xbp-1 loss reduces lifespan. However, lifespan effects are downstream of the primary ER proteostasis function. The mechanism involves improved stress resistance and proteostasis maintenance. Supporting Evidence: PMID:23791175 Neuronally derived XBP-1s was sufficient to rescue stress resistance, increase longevity, and activate the UPR(ER) in distal, non-neuronal cell types UniProt:G5EE07 Reduces lifespan, perhaps acting independently of macroautophagy |
| GO:0009408 response to heat | IGI PMID:22125500 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabdi... | ACCEPT | Summary: Richardson et al. (2011) showed temperature-dependent synthetic lethality between xbp-1 and pek-1 mutations. The requirement for XBP-1 and PEK-1 increases at elevated physiological temperatures. Reason: Well-supported by IGI evidence. The xbp-1;pek-1 double mutant shows temperature-sensitive lethality, with more severe phenotypes at higher temperatures. This reflects increased ER stress and proteostatic demands at elevated temperatures requiring UPR function. Supporting Evidence: PMID:22125500 We define a dynamic, temperature-dependent requirement for XBP-1 and PEK-1 activities PMID:22125500 Temperature-sensitive lethality of the xbp-1;pek-1 double mutant |
| GO:0034976 response to endoplasmic reticulum stress | IGI PMID:22125500 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabdi... | ACCEPT | Summary: Richardson et al. (2011) used genetic interaction analysis to show that XBP-1 functions in the response to ER stress. The synthetic lethality between xbp-1 and pek-1 demonstrates complementary ER stress response pathways. Reason: This is a core biological process for XBP-1. The IGI evidence from genetic interactions with pek-1 and atf-6 demonstrates that XBP-1 is essential for ER stress response in combination with other UPR branches. Supporting Evidence: PMID:22125500 XBP-1 and PEK-1 each protect against elevated physiological temperature and immune activity |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:23791175 XBP-1 is a cell-nonautonomous regulator of stress resistance... | ACCEPT | Summary: Taylor and Dillin (2013) showed that XBP-1s rescues age-onset loss of ER proteostasis and that neuronal XBP-1s activates the UPR in distal tissues. Reason: Core biological process. The paper demonstrates XBP-1s can rescue stress resistance and that the UPR pathway functions cell-nonautonomously through XBP-1 signaling. Supporting Evidence: PMID:23791175 age-onset loss of ER proteostasis could be reversed by expression of a constitutively active form of XBP-1, XBP-1s |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:22125500 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabdi... | KEEP AS NON CORE | Summary: Richardson et al. (2011) showed that XBP-1 is required for protecting the host during innate immune responses. The xbp-1 mutant cannot tolerate the ER stress induced by immune activation. Reason: This is an important but indirect role. XBP-1 does not directly mediate immune defense; rather, it protects against the ER stress caused by the secretory demands of mounting an immune response. The primary role is maintaining ER homeostasis during immune activation. Supporting Evidence: PMID:22125500 XBP-1 and PEK-1 Maintain Intestinal Cell Homeostasis during ER Stress Caused by Basal and Induced Innate Immunity PMID:20182512 an ancient, conserved role for XBP-1 may be to protect the host organism from the detrimental effects of mounting an innate immune response to microbes |
| GO:0034976 response to endoplasmic reticulum stress | IMP PMID:20182512 An essential role for XBP-1 in host protection against immun... | ACCEPT | Summary: Richardson et al. (2010) demonstrated that XBP-1 is essential for protection against ER stress induced by innate immune activation. The xbp-1 mutant shows disrupted ER morphology upon P. aeruginosa infection. Reason: Strong IMP evidence for core function. The paper shows xbp-1 mutants have ER disruption during immune stress, and this phenotype is rescued by reducing the immune response (pmk-1 mutation), demonstrating XBP-1's essential role in ER stress response. Supporting Evidence: PMID:20182512 xbp-1(zc12) larvae propagated on P. aeruginosa PA14 revealed disruption in ER morphology PMID:20182512 the xbp-1(zc12) mutant on P. aeruginosa exhibited severely attenuated larval development and growth, as measured by the rate of progression between molts |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:20182512 An essential role for XBP-1 in host protection against immun... | KEEP AS NON CORE | Summary: Richardson et al. (2010) showed that xbp-1 mutants have attenuated development on P. aeruginosa, but this is due to inability to tolerate immune activation rather than direct immune function. Reason: The annotation captures a genuine phenotype but the mechanism is indirect. XBP-1 does not directly mediate defense; it protects against self-inflicted ER stress from immune activation. Importantly, diminishing the immune response actually improves the survival of the xbp-1 mutant on P. aeruginosa (PMID:20182512). Supporting Evidence: PMID:20182512 the principal mechanism by which XBP-1 promotes development and survival during infection with P. aeruginosa is by protecting against the innate immune response PMID:20182512 the xbp-1;pmk-1 double mutant showed markedly increased development and survival relative to the xbp-1 mutant |
| GO:0036498 IRE1-mediated unfolded protein response | IMP PMID:23791175 XBP-1 is a cell-nonautonomous regulator of stress resistance... | ACCEPT | Summary: Taylor and Dillin (2013) showed that XBP-1s functions in the IRE-1-mediated UPR, with neuronal expression activating UPR in distal tissues. Reason: Core biological process. The paper confirms XBP-1s as the active form produced by IRE-1-mediated splicing that drives UPR transcription. Supporting Evidence: PMID:23791175 expression of a constitutively active form of XBP-1, XBP-1s PMID:23791175 activate the UPR(ER) in distal, non-neuronal cell types through a cell-nonautonomous mechanism |
| GO:0000977 RNA polymerase II transcription regulatory region sequence-specific DNA binding | IDA PMID:24068940 Integration of the unfolded protein and oxidative stress res... | ACCEPT | Summary: Glover-Cutter et al. (2013) performed ChIP analysis showing that SKN-1 and XBP-1 bind to common downstream targets during the UPR. This provides direct evidence for XBP-1 DNA binding at target gene promoters. Reason: Strong IDA evidence for sequence-specific DNA binding. The paper shows XBP-1 ChIP occupancy at promoters of UPR target genes, demonstrating direct DNA binding activity. This confirms the core molecular function of XBP-1 as a sequence-specific transcription factor. Supporting Evidence: PMID:24068940 binds to common downstream targets with XBP-1 and ATF-6 |
| GO:0036498 IRE1-mediated unfolded protein response | IEP PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Shen et al. (2001) showed that xbp-1 mRNA is spliced by IRE-1 during ER stress, and this spliced form is required for UPR gene transcription. Reason: Core biological process. The foundational paper establishes that xbp-1 mRNA undergoes IRE-1-mediated unconventional splicing during ER stress, producing the active transcription factor. IEP evidence supports expression pattern consistent with this role. Supporting Evidence: PMID:11779465 C. elegans requires ire-1-mediated splicing of xbp-1 mRNA for UPR gene transcription and survival upon ER stress |
| GO:0036498 IRE1-mediated unfolded protein response | IGI PMID:11779465 Complementary signaling pathways regulate the unfolded prote... | ACCEPT | Summary: Shen et al. (2001) demonstrated genetic interactions showing xbp-1 functions downstream of ire-1 and in parallel with pek-1 for development. Reason: Core biological process. IGI evidence from synthetic lethal interactions with pek-1 demonstrates XBP-1's essential role in the IRE-1 branch of the UPR. Supporting Evidence: PMID:11779465 ire-1/xbp-1 acts with pek-1, a protein kinase that mediates translation attenuation, in complementary pathways that are essential for worm development and survival |
| GO:0036498 IRE1-mediated unfolded protein response | IMP PMID:25298520 Developmental defects in a Caenorhabditis elegans model for ... | ACCEPT | Summary: Brokate-Llanos et al. (2014) found interactions between gale-1 (galactosemia model) and the UPR, with xbp-1 involved in the response to glycosylation defects. Reason: Supports the core function of XBP-1 in UPR. The paper shows genetic interactions between the UPR and galactose metabolism/glycosylation, consistent with XBP-1's role in responding to ER stress caused by glycosylation defects. Supporting Evidence: PMID:25298520 we found interactions between gale-1 and the unfolded protein response |
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Download this section (compressed HTML)Q: What is the exact mechanism by which neuronal XBP-1s signals to distal tissues to activate UPR cell-nonautonomously? Taylor and Dillin (2013) showed neurotransmitter release is required, but the identity of the secreted ER stress signal (SERSS) remains unknown.
Q: Are there specific DNA sequences (UPREs) that XBP-1 binds in C. elegans, and do they differ from mammalian XBP1 binding sites? While ChIP evidence exists, the specific binding motifs for C. elegans XBP-1 have not been comprehensively characterized.
Experiment: ChIP-seq of XBP-1s to comprehensively map DNA binding sites across the genome during ER stress. This would provide genome-wide identification of direct XBP-1 target genes and binding motif characterization.
Experiment: Tissue-specific rescue experiments to determine which tissues require XBP-1 for different phenotypes (development, immunity, lifespan). This would clarify the cell-autonomous vs cell-nonautonomous requirements for XBP-1 function.
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