ZIP-2 is a bZIP transcription factor of the C/EBP subfamily that plays a central role in C. elegans surveillance immunity. It functions as a key mediator of the host response to translational inhibition caused by pathogen-derived toxins, particularly P. aeruginosa Exotoxin A. ZIP-2 acts together with CEBP-2 to activate infection response genes including irg-1 and irg-2. The protein is also part of the ESRE (Ethanol and Stress Response Element) network that responds to mitochondrial damage. ZIP-2 is induced by P. aeruginosa infection and by translational inhibitors such as cycloheximide. Loss of zip-2 results in decreased survival upon P. aeruginosa infection and reduced induction of infection response genes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IBA GO_REF:0000033 | ACCEPT | Summary: ZIP-2 is a bZIP transcription factor that binds DNA to regulate transcription of target genes including infection response genes (irg-1, irg-2). The bZIP domain (aa 242-305) contains a basic motif (aa 246-276) and leucine-zipper (aa 277-291) characteristic of sequence-specific DNA binding transcription factors. Reason: This annotation is phylogenetically supported and consistent with ZIP-2's demonstrated role as a transcription factor that regulates expression of specific target genes. UniProt notes that ZIP-2 "binds to the promoter and the enhancer regions of target genes" (by similarity). The presence of a canonical bZIP domain with basic motif supports DNA binding function. Supporting Evidence: UniProtKB:Q21148 DOMAIN 242..305 /note="bZIP" /evidence="ECO:0000255|PROSITE-ProRule:PRU00978" file:worm/zip-2/zip-2-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ZIP-2 regulates transcription of infection response genes and ESRE network genes in response to pathogen exposure and cellular stress. The IBA annotation is phylogenetically supported and consistent with experimental evidence showing ZIP-2-dependent gene expression changes. Reason: Experimental evidence strongly supports this annotation. PMID:20133860 demonstrated that zip-2 is required for induction of irg-1 and other genes upon P. aeruginosa infection. PMID:28662060 showed ZIP-2 regulates ESRE gene expression in response to mitochondrial damage. PMID:25274306 showed zip-2 is required for irg-1 induction during UPRmt activation. Supporting Evidence: PMID:20133860 This screen identified zip-2, a bZIP transcription factor that is required for inducing irg-1, as well as several other genes PMID:28662060 Loss of ZIP-2, ZIP-4, or CEBP-1 individually was sufficient to compromise ESRE gene induction |
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: ZIP-2 functions as a DNA-binding transcription factor that activates Pol II-dependent transcription of target genes. This IBA annotation correctly captures ZIP-2's molecular function as a transcription factor. Reason: ZIP-2 has a canonical bZIP domain and functions to activate transcription of target genes including infection response genes. Experimental evidence from multiple studies confirms its role as a transcriptional activator. The phylogenetic inference is well-supported. Supporting Evidence: PMID:20133860 zip-2, a bZIP transcription factor that is required for inducing irg-1 UniProtKB:Q21148 Belongs to the bZIP family. C/EBP subfamily |
| GO:0002376 immune system process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: This IEA annotation from UniProt keyword mapping captures ZIP-2's role in immunity but is overly broad. More specific terms are available and already annotated. Reason: While ZIP-2 is clearly involved in immune processes, this term is too general. The more specific annotations to GO:0140367 (antibacterial innate immune response) and GO:0045087 (innate immune response) better capture ZIP-2's role. This annotation is not wrong but adds little value beyond the more specific terms. Supporting Evidence: UniProtKB:Q21148 Has a protective role in response to infection by the Gram-negative bacterium P.aeruginosa |
| GO:0003677 DNA binding | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: This IEA annotation is consistent with ZIP-2's bZIP domain but is superseded by the more specific IBA annotation to GO:0000978 (RNA polymerase II cis-regulatory region sequence-specific DNA binding). Reason: The annotation is correct but too general. GO:0000978 and GO:0000981 are more informative and already annotated via IBA. This generic DNA binding term adds little value. Supporting Evidence: UniProtKB:Q21148 DOMAIN 242..305 /note="bZIP" |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: This InterPro-derived annotation captures ZIP-2's function as a transcription factor but is superseded by the more specific IBA annotation GO:0000981. Reason: Correct but too general. GO:0000981 (DNA-binding transcription factor activity, RNA polymerase II-specific) provides more specificity and is already annotated via IBA. Supporting Evidence: GO_REF:0000002 InterPro:IPR004827|InterPro:IPR031106|InterPro:IPR046347 |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: ZIP-2 localizes to the nucleus where it functions as a transcription factor. Nuclear localization is experimentally demonstrated in the literature. Reason: Nuclear localization is well-supported experimentally. PMID:22520465 showed nuclear accumulation of ATFS-1::GFP requires NLS. UniProt cites PMID:22520465 and PMID:26876169 as evidence for nuclear localization of ZIP-2. Supporting Evidence: UniProtKB:Q21148 SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:22520465, ECO:0000269|PubMed:26876169} |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: This combined automated annotation captures ZIP-2's involvement in transcription but is superseded by more specific terms already annotated. Reason: The annotation is correct but too general. GO:0006357 (regulation of transcription by RNA polymerase II) and GO:0045944 (positive regulation of transcription by RNA polymerase II) provide more specific and informative annotations that are already present. Supporting Evidence: UniProtKB:Q21148 Required for the activation of several infection response genes including irg-1 and irg-2 |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: This InterPro-derived annotation is superseded by the more specific GO:0006357 and GO:0045944 annotations already present. Reason: Correct but too general. More specific annotations to GO:0006357 (IBA) and GO:0045944 (IMP) are already present and provide more information about ZIP-2's transcriptional function. Supporting Evidence: GO_REF:0000002 InterPro:IPR004827|InterPro:IPR046347 |
| GO:0045087 innate immune response | IEA GO_REF:0000043 | ACCEPT | Summary: ZIP-2 is involved in innate immune response, specifically surveillance immunity that detects pathogen-induced cellular perturbations. This is a core function of the protein. Reason: ZIP-2's role in innate immunity is well-established experimentally. It mediates the protective response to P. aeruginosa infection by activating infection response genes. While GO:0140367 (antibacterial innate immune response) is more specific and also annotated, this term is appropriate for the broader innate immune function. Supporting Evidence: PMID:20133860 zip-2 is part of a specialized pathogen response pathway that is induced by virulent strains of P. aeruginosa and provides defense against this pathogen PMID:26876169 CEBP-2 acts together with the bZIP transcription factor ZIP-2 in the protective response to translational block by P. aeruginosa Exotoxin A |
| GO:0050829 defense response to Gram-negative bacterium | IEA GO_REF:0000117 | ACCEPT | Summary: This ARBA-derived annotation correctly captures ZIP-2's role in defense against the Gram-negative bacterium P. aeruginosa. Multiple IMP annotations to the same term provide experimental support. Reason: This annotation is well-supported by experimental evidence. Multiple publications demonstrate ZIP-2's role in defense against P. aeruginosa (Gram-negative). The IEA annotation is consistent with the IMP annotations to the same term. Supporting Evidence: PMID:20133860 is important for defense against infection by P. aeruginosa |
| GO:0005515 protein binding | IPI PMID:23661758 Networks of bZIP protein-protein interactions diversified ov... | MODIFY | Summary: This annotation records physical interaction between ZIP-2 and ATF-2, demonstrated by in vitro protein-protein interaction assays studying bZIP dimerization networks. Reason: While the physical interaction with ATF-2 is experimentally demonstrated, the generic "protein binding" term is uninformative. As a bZIP transcription factor, ZIP-2 forms dimers with other bZIP proteins. A more specific term like GO:0046983 (protein dimerization activity) or GO:0042803 (protein homodimerization activity) would be more appropriate given that bZIP proteins function as dimers. Proposed replacements: protein dimerization activity Supporting Evidence: PMID:23661758 We studied the basic region-leucine zipper (bZIP) transcription factors and quantified bZIP dimerization networks for five metazoan and two single-cell species |
| GO:0005515 protein binding | IPI PMID:23791784 Extensive rewiring and complex evolutionary dynamics in a C.... | MODIFY | Summary: This annotation records physical interaction between ZIP-2 and CEBP-2, which is functionally significant as these proteins work together in surveillance immunity. Reason: The interaction with CEBP-2 is well-documented and functionally important. PMID:26876169 shows CEBP-2 and ZIP-2 "act together" in surveillance immunity. However, "protein binding" is too generic for bZIP dimerization. A more informative term would be protein dimerization activity, as bZIP proteins form obligate dimers for DNA binding. Proposed replacements: protein dimerization activity Supporting Evidence: PMID:26876169 CEBP-2 acts together with the bZIP transcription factor ZIP-2 in the protective response to translational block UniProtKB:Q21148 Q21148; Q8IG69: cebp-2; NbExp=3 |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:28662060 A conserved mitochondrial surveillance pathway is required f... | ACCEPT | Summary: PMID:28662060 demonstrates that zip-2 mutants show increased sensitivity to P. aeruginosa in liquid killing assays, supporting a protective role against this Gram-negative pathogen. Reason: The paper demonstrates that loss of zip-2 compromises survival during P. aeruginosa exposure in liquid killing conditions. ZIP-2 is part of a family of bZIP transcription factors (including ZIP-4, CEBP-1, CEBP-2) that mediate the ESRE defense network. Supporting Evidence: PMID:28662060 RNAi targeting any of these four bZIP family members significantly compromised survival in Liquid Killing PMID:28662060 glp-4(bn2); zip-2(tm4248)...showed increased sensitivity to Liquid Killing |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:20133860 bZIP transcription factor zip-2 mediates an early response t... | ACCEPT | Summary: ZIP-2 positively regulates transcription of infection response genes including irg-1. This is a core function supported by direct experimental evidence. Reason: The annotation is well-supported by the cited reference. PMID:20133860 showed that zip-2 is required for inducing irg-1 expression in response to P. aeruginosa infection. Loss of zip-2 reduces irg-1 induction, demonstrating positive regulation. Supporting Evidence: PMID:20133860 zip-2, a bZIP transcription factor that is required for inducing irg-1, as well as several other genes UniProtKB:Q21148 Required for the activation of several infection response genes including irg-1 and irg-2 |
| GO:0140367 antibacterial innate immune response | IMP PMID:20133860 bZIP transcription factor zip-2 mediates an early response t... | ACCEPT | Summary: ZIP-2 is required for the antibacterial innate immune response, specifically the protective response to P. aeruginosa infection. This is a core function. Reason: ZIP-2 is central to the C. elegans surveillance immunity pathway that detects and responds to bacterial pathogens. Loss of zip-2 decreases survival upon P. aeruginosa infection and reduces induction of infection response genes. Supporting Evidence: PMID:20133860 zip-2 is part of a specialized pathogen response pathway that is induced by virulent strains of P. aeruginosa and provides defense against this pathogen UniProtKB:Q21148 Has a protective role in response to infection by the Gram-negative bacterium P.aeruginosa |
| GO:0050829 defense response to Gram-negative bacterium | IGI PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: This IGI annotation records genetic interaction between zip-2 and atfs-1 in the defense response to P. aeruginosa. ATFS-1 regulates zip-2 expression during infection. Reason: The genetic interaction between zip-2 and atfs-1 is well-documented. PMID:25274306 showed that zip-2 mRNA is induced during mitochondrial stress in an atfs-1-dependent manner, and that both transcription factors contribute to defense against P. aeruginosa. Supporting Evidence: PMID:25274306 zip-2 mRNA was induced during mitochondrial stress, which also required atfs-1 PMID:25274306 increased irg-1pr::gfp expression was impaired in both atfs-1(tm4919) and zip-2(tm4248) mutants |
| GO:0010628 positive regulation of gene expression | IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | KEEP AS NON CORE | Summary: ZIP-2 positively regulates expression of infection response genes. This annotation overlaps with GO:0045944 but is at a broader level. Reason: While correct, this term is less specific than GO:0045944 (positive regulation of transcription by RNA polymerase II) which better captures ZIP-2's mechanism of action. The annotation is valid but represents a more general characterization of ZIP-2 function. Supporting Evidence: PMID:25274306 irg-1pr::gfp induction, which was blocked in atfs-1(tm4919) and partially so in zip-2(tm4248) worms |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:25274306 Mitochondrial UPR-regulated innate immunity provides resista... | ACCEPT | Summary: Experimental evidence from PMID:25274306 demonstrates ZIP-2's role in defense against P. aeruginosa through the UPRmt-regulated innate immunity pathway. Reason: This annotation is supported by experimental evidence showing that zip-2 mutants have impaired infection response gene induction. ZIP-2 is part of the protective transcriptional response activated by mitochondrial stress during pathogen exposure. Supporting Evidence: PMID:25274306 zip-2(tm4248) modestly reduced the enhanced resistance conferred by spg-7(RNAi) |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:20133860 bZIP transcription factor zip-2 mediates an early response t... | ACCEPT | Summary: The foundational paper establishing ZIP-2's role in defense against P. aeruginosa. zip-2 knockdown decreases survival upon infection. Reason: PMID:20133860 is the key paper identifying ZIP-2 as a mediator of early response to P. aeruginosa infection. The paper demonstrates that zip-2 is required for defense through RNAi knockdown and survival assays. Supporting Evidence: PMID:20133860 is important for defense against infection by P. aeruginosa UniProtKB:Q21148 RNAi-mediated knockdown decreases survival upon infection with P.aeruginosa |
Loading supporting content…
Download this section (compressed HTML)Q: What are the direct DNA binding sites/motifs recognized by ZIP-2?
Q: Does ZIP-2 form homodimers or only heterodimers with other bZIP proteins?
Q: What is the complete set of target genes directly regulated by ZIP-2?
Q: How is ZIP-2 itself regulated at the post-translational level?
Experiment: ChIP-seq to identify direct ZIP-2 target genes and binding sites
Experiment: Structural studies of ZIP-2/CEBP-2 heterodimer to understand specificity
Experiment: Time-course RNA-seq in zip-2 mutants during infection to identify direct targets
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)