ATF-7 is a CREB/ATF family bZIP transcription factor that functions as the key downstream effector of the PMK-1 p38 MAPK innate immune signaling pathway in C. elegans. It is a direct substrate of PMK-1 and undergoes phosphorylation-dependent switching from a transcriptional repressor to an activator upon pathogen infection. ATF-7 binds to CRE-like DNA elements (5'-GACgTCA-3' consensus) and directly regulates the transcription of over 50% of all pathogen-induced genes, including antimicrobial effectors such as C-type lectins and lysozymes. Beyond innate immunity, ATF-7 also regulates serotonin biosynthesis in ADF chemosensory neurons and metallothionein expression in response to metal ions and oxidative stress. ATF-7 cooperates with the GATA transcription factor ELT-2 for p38-dependent immune gene induction in the intestine. It is expressed primarily in intestinal cells and localizes to the nucleus and chromatin.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000981 DNA-binding transcription factor activity, RNA polymerase II-specific | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-7 is a bZIP transcription factor that directly binds DNA and regulates RNA polymerase II-mediated transcription. ChIP-seq demonstrated ATF-7 binding to promoter regions of target genes in a PMK-1-dependent manner (PMID:30789901). Reason: This annotation is strongly supported by phylogenetic inference and experimental evidence. ATF-7 is orthologous to mammalian ATF2/ATF7 family members which are established DNA-binding transcription factors. ChIP-seq data confirmed ATF-7 binding at promoter regions containing CRE-like motifs (PMID:30789901). Supporting Evidence: PMID:30789901 MEME analysis of the most enriched loci identified significant enrichment for the motif GACgTCA, which corresponds to the Jun D bZIP motif expected for ATF-7 (Fig 2A, S3B Fig) PMID:20369020 ATF-7, a putative ortholog of the mammalian ATF2 family of basic-region leucine zipper (bZIP) transcription factors file:worm/atf-7/atf-7-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0006357 regulation of transcription by RNA polymerase II | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-7 regulates transcription by RNA polymerase II, controlling both basal repression and pathogen-induced activation of target genes (PMID:20369020, PMID:30789901). Reason: Phylogenetic inference is well-supported by experimental data. ATF-7 loss-of-function and gain-of-function mutants show altered transcription of PMK-1-regulated genes, and ChIP-seq confirms ATF-7 occupancy at promoters of pathogen-induced genes. Supporting Evidence: PMID:20369020 ATF-7 functions as a repressor of PMK-1-regulated genes that undergoes a switch to an activator upon phosphorylation by PMK-1 |
| GO:0035497 cAMP response element binding | IBA GO_REF:0000033 | ACCEPT | Summary: ATF-7 binds CRE-like DNA sequences. ChIP-seq motif analysis identified the 5'-GACgTCA-3' consensus sequence in ATF-7 binding sites, which is a CRE-like element characteristic of ATF/CREB family members (PMID:30789901). Reason: This annotation is strongly supported by ChIP-seq data showing ATF-7 binding to CRE-like motifs. The motif identified (GACgTCA) closely matches the canonical CRE sequence, consistent with ATF-7's membership in the CREB/ATF family. Supporting Evidence: PMID:30789901 MEME analysis of the most enriched loci identified significant enrichment for the motif GACgTCA, which corresponds to the Jun D bZIP motif expected for ATF-7 (Fig 2A, S3B Fig). This motif is present in as many as 80% of the most highly enriched regions of the genome |
| GO:0003700 DNA-binding transcription factor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Inferred from InterPro domains (bZIP domain). ATF-7 contains a conserved bZIP domain that mediates DNA binding and dimerization. Reason: This IEA annotation based on InterPro is correct but less specific than the IBA annotation for RNA polymerase II-specific DNA-binding TF activity. Both are valid and supported by experimental evidence. Supporting Evidence: PMID:20369020 ATF-7, a member of the conserved cyclic AMP-responsive element binding (CREB)/activating transcription factor (ATF) family of basic-region leucine zipper (bZIP) transcription factors |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: ATF-7 localizes to the nucleus. This IEA annotation is supported by experimental evidence from GFP fusion localization studies (PMID:20369020). Reason: The IEA annotation is correct and backed by direct experimental evidence. ATF-7::GFP is strongly expressed in nuclei of intestinal cells. Supporting Evidence: PMID:20369020 We observed that a rescuing translational fusion of ATF-7::GFP under the control of the endogenous promoter and 3′ UTR was strongly expressed in the nuclei of intestinal cells |
| GO:0005694 chromosome | IEA GO_REF:0000044 | ACCEPT | Summary: ATF-7 associates with chromosomes/chromatin as demonstrated by ChIP-seq studies (PMID:30789901). Reason: This IEA annotation is supported by ChIP-seq data showing ATF-7 binding to chromatin at thousands of genomic loci. Supporting Evidence: PMID:30789901 In all conditions analyzed, ATF-7 exhibited abundant association throughout the genome, with 8,962 total peaks identified as enriched by MACS2 |
| GO:0006351 DNA-templated transcription | IEA GO_REF:0000043 | ACCEPT | Summary: ATF-7 is involved in DNA-templated transcription as a transcriptional regulator. This general term is subsumed by more specific annotations. Reason: Correct annotation based on UniProt keywords, though less specific than other annotations for regulation of transcription. |
| GO:0006355 regulation of DNA-templated transcription | IEA GO_REF:0000002 | ACCEPT | Summary: ATF-7 regulates DNA-templated transcription. Inferred from InterPro bZIP domain. Reason: Correct annotation based on domain analysis. ATF-7 functions as a transcriptional regulator, both repressing and activating transcription depending on its phosphorylation state. |
| GO:0000785 chromatin | IDA PMID:30789901 Global transcriptional regulation of innate immunity by ATF-... | ACCEPT | Summary: ATF-7 associates with chromatin as demonstrated by ChIP-seq. The study used ATF-7::GFP for chromatin immunoprecipitation, showing ATF-7 binding at thousands of genomic loci (PMID:30789901). Reason: Direct experimental evidence from ChIP-seq demonstrates ATF-7 chromatin association. The study identified 8,962 ATF-7 binding peaks across the genome. Supporting Evidence: PMID:30789901 we performed chromatin immunoprecipitation followed by sequencing (ChIP-seq) of animals carrying a GFP-tag fused to the C-terminal end of the endogenous atf-7 locus |
| GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding | IMP PMID:30789901 Global transcriptional regulation of innate immunity by ATF-... | ACCEPT | Summary: ATF-7 binds to cis-regulatory regions of genes in a sequence-specific manner. ChIP-seq identified ATF-7 binding at promoter regions containing the CRE-like motif GACgTCA, and loss of atf-7 abrogates pathogen-induced gene expression (PMID:30789901). Reason: Strong experimental evidence. ChIP-seq combined with motif analysis demonstrated that ATF-7 binds specifically to CRE-like elements in promoter regions. RNA-seq in atf-7 mutants confirmed that ATF-7 binding corresponds to transcriptional regulation. Supporting Evidence: PMID:30789901 ATF-7 is preferentially located at the promoter regions of genes that are increased in expression by P. aeruginosa, and that this enrichment for ATF-7 is lessened by pmk-1 loss |
| GO:0006357 regulation of transcription by RNA polymerase II | IMP PMID:30789901 Global transcriptional regulation of innate immunity by ATF-... | ACCEPT | Summary: ATF-7 regulates transcription by RNA polymerase II. Loss of atf-7 abrogates pathogen-induced gene expression, and ATF-7 regulates over 50% of all pathogen-induced genes (PMID:30789901). Reason: Strong experimental evidence from RNA-seq analysis showing ATF-7-dependent regulation of pathogen-induced genes. This experimental annotation provides direct evidence complementing the IBA annotation. Supporting Evidence: PMID:30789901 We observed that 70% of genes significantly induced two-fold or greater by P. aeruginosa exposure were no longer fully induced upon loss of pmk-1, and that 53% of upregulated genes were no longer fully induced upon loss of atf-7 |
| GO:0010468 regulation of gene expression | IMP PMID:26016853 The Developmental Intestinal Regulator ELT-2 Controls p38-De... | ACCEPT | Summary: ATF-7 regulates gene expression downstream of p38 MAPK signaling. ELT-2 cooperates with ATF-7 for p38-dependent immune gene induction (PMID:26016853). Reason: This annotation is supported but is less specific than other annotations. ATF-7 regulates gene expression as a transcription factor downstream of PMK-1. Supporting Evidence: PMID:26016853 elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1 |
| GO:0010468 regulation of gene expression | IMP PMID:28632756 Identification of ATF-7 and the insulin signaling pathway in... | ACCEPT | Summary: ATF-7 regulates gene expression, specifically metallothionein gene mtl-1 transcription in response to cadmium and oxidative stress (PMID:28632756). Reason: ATF-7 was identified as a regulator of mtl-1 metallothionein expression in both mutagenesis and candidate gene screens. This demonstrates ATF-7's role in regulating gene expression beyond innate immunity. Supporting Evidence: PMID:28632756 The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens |
| GO:0034614 cellular response to reactive oxygen species | IMP PMID:28632756 Identification of ATF-7 and the insulin signaling pathway in... | ACCEPT | Summary: ATF-7 is involved in the response to reactive oxygen species through its regulation of metallothionein expression. Metallothioneins function as ROS scavengers (PMID:28632756). Reason: ATF-7 regulates metallothionein mtl-1, which functions as a ROS scavenger. This represents a legitimate role for ATF-7 in cellular response to oxidative stress, though the primary function is through transcriptional regulation. Supporting Evidence: PMID:28632756 Metallothioneins are conserved cysteine-rich proteins that function as efficient ROS scavengers and may affect longevity |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:23505381 RFX transcription factor DAF-19 regulates 5-HT and innate im... | ACCEPT | Summary: ATF-7 is required for defense response to Gram-negative bacteria including P. aeruginosa. ATF-7 works downstream of TIR-1 signaling in both innate immunity and serotonin biosynthesis responses (PMID:23505381). Reason: Core function of ATF-7. The study shows ATF-7 functions with DAF-19 in TIR-1-dependent innate immune responses to pathogenic bacteria. Supporting Evidence: PMID:23505381 common transcription factors control the innate immunity and 5-HT biosynthesis |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:26016853 The Developmental Intestinal Regulator ELT-2 Controls p38-De... | ACCEPT | Summary: ATF-7 cooperates with ELT-2 for p38-dependent immune responses to P. aeruginosa infection (PMID:26016853). Reason: Core function. ATF-7 is a key effector of the p38 MAPK pathway in antibacterial innate immunity. Supporting Evidence: PMID:26016853 elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1 |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:30789901 Global transcriptional regulation of innate immunity by ATF-... | ACCEPT | Summary: ATF-7 is essential for defense response to Gram-negative bacteria. Genome-wide analysis showed ATF-7 regulates the majority of pathogen-induced genes in response to P. aeruginosa (PMID:30789901). Reason: Core function. This study provides the most comprehensive evidence that ATF-7 is the primary transcriptional regulator of innate immunity downstream of PMK-1 p38 MAPK. Supporting Evidence: PMID:30789901 PMK-1-ATF-7 signaling regulates over half of all pathogen-induced genes at the genome-wide level |
| GO:0071248 cellular response to metal ion | IMP PMID:28632756 Identification of ATF-7 and the insulin signaling pathway in... | ACCEPT | Summary: ATF-7 is involved in the cellular response to metal ions, specifically regulating metallothionein mtl-1 expression in response to cadmium (PMID:28632756). Reason: ATF-7 was identified as a regulator of cadmium-inducible metallothionein expression. This represents a legitimate non-immune function of ATF-7. Supporting Evidence: PMID:28632756 the regulatory factors and pathways that controlled cadmium-inducible transcription of the C. elegans metallothionein gene, mtl-1, were identified. The transcription factor ATF-7 was identified |
| GO:0042427 serotonin biosynthetic process | IMP PMID:23505381 RFX transcription factor DAF-19 regulates 5-HT and innate im... | KEEP AS NON CORE | Summary: ATF-7 is involved in serotonin biosynthesis regulation. It works with DAF-19 downstream of TIR-1 signaling to regulate tph-1 expression in ADF neurons in response to pathogenic bacteria (PMID:23505381). Reason: While ATF-7 does regulate serotonin biosynthesis gene tph-1 in ADF neurons, this appears to be a specialized function in the context of pathogen sensing rather than a core metabolic function. The primary role of ATF-7 is as a transcriptional regulator of innate immunity. Supporting Evidence: PMID:23505381 TIR-1-induced tph-1 upregulation requires DAF-19 and ATF-7 |
| GO:0140367 antibacterial innate immune response | IMP PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 is essential for the antibacterial innate immune response. It is phosphorylated by PMK-1 p38 MAPK and switches from a transcriptional repressor to activator to induce immune effector genes (PMID:20369020). Reason: Core function of ATF-7. This seminal paper established ATF-7 as the key transcriptional effector of the PMK-1 innate immune pathway. Supporting Evidence: PMID:20369020 elegans ATF-7, a member of the conserved cyclic AMP-responsive element binding (CREB)/activating transcription factor (ATF) family of basic-region leucine zipper (bZIP) transcription factors and an ortholog of mammalian ATF2/ATF7, has a pivotal role in the regulation of PMK-1-mediated innate immunity |
| GO:0005634 nucleus | IDA PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7::GFP localizes to the nucleus of intestinal cells (PMID:20369020). Reason: Direct experimental evidence. Fluorescence microscopy of ATF-7::GFP translational fusion demonstrated strong nuclear localization. Supporting Evidence: PMID:20369020 We observed that a rescuing translational fusion of ATF-7::GFP under the control of the endogenous promoter and 3′ UTR was strongly expressed in the nuclei of intestinal cells |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IMP PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 functions as a transcriptional repressor in its unphosphorylated state. Loss-of-function atf-7 mutants restore expression of PMK-1-regulated genes in pmk-1 null mutants, indicating ATF-7 acts as a repressor that is relieved by PMK-1 phosphorylation (PMID:20369020). Reason: Core function. ATF-7 has dual activity - repressor and activator - depending on its phosphorylation state. The repressor function is essential for controlling basal expression of immune genes. Supporting Evidence: PMID:20369020 ATF-7 functions as a repressor of PMK-1-regulated genes that undergoes a switch to an activator upon phosphorylation by PMK-1 |
| GO:0003700 DNA-binding transcription factor activity | ISS PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 is orthologous to mammalian ATF2 and functions as a DNA-binding transcription factor (PMID:20369020). Reason: Sequence similarity to mammalian ATF2 is supported by extensive experimental evidence demonstrating ATF-7's function as a DNA-binding transcription factor. Supporting Evidence: PMID:20369020 ATF-7, a putative ortholog of the mammalian ATF2 family of basic-region leucine zipper (bZIP) transcription factors |
| GO:0045089 positive regulation of innate immune response | IMP PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 positively regulates innate immune response when phosphorylated by PMK-1. Loss of atf-7 abrogates pathogen-induced gene expression even though it relieves repression of basal expression (PMID:20369020). Reason: Core function. ATF-7's activator function is essential for mounting the pathogen-induced immune response. Supporting Evidence: PMID:20369020 the induction of PMK-1-regulated genes by pathogenic Pseudomonas aeruginosa PA14 is abrogated |
| GO:0045824 negative regulation of innate immune response | IMP PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 negatively regulates innate immune response in its unphosphorylated state by repressing basal expression of immune genes. Loss of atf-7 de-represses PMK-1-regulated genes (PMID:20369020). Reason: Core function. ATF-7's repressor function is important for preventing constitutive activation of immune genes, which would be detrimental. Supporting Evidence: PMID:20369020 The loss-of-function atf-7(qd22 qd130) mutation suppresses the immunodeficient phenotype caused by deficient signaling in the PMK-1 pathway |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IMP PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 positively regulates transcription by RNA polymerase II when phosphorylated by PMK-1, activating expression of immune effector genes (PMID:20369020). Reason: Core function. ATF-7 switches to an activator upon phosphorylation by PMK-1, directly inducing transcription of target genes. Supporting Evidence: PMID:20369020 ATF-7 functions as a repressor of PMK-1-regulated genes that undergoes a switch to an activator upon phosphorylation by PMK-1 |
| GO:0050829 defense response to Gram-negative bacterium | IMP PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 is essential for defense response to Gram-negative bacteria. atf-7 mutants show enhanced susceptibility to P. aeruginosa (PMID:20369020). Reason: Core function. This is the primary physiological role of ATF-7, supported by multiple independent studies. Supporting Evidence: PMID:20369020 loss of atf-7 activity also compromises pathogen resistance relative to WT |
| GO:0051019 mitogen-activated protein kinase binding | IPI PMID:20369020 Phosphorylation of the conserved transcription factor ATF-7 ... | ACCEPT | Summary: ATF-7 physically interacts with PMK-1 p38 MAPK. Co-immunoprecipitation experiments in Cos7 cells demonstrated ATF-7 binding to activated PMK-1 (PMID:20369020). Reason: Core function. Physical interaction with PMK-1 is essential for ATF-7's phosphorylation and functional switch from repressor to activator. Supporting Evidence: PMID:20369020 We used a mutated version of PMK-1 that does not have kinase activity to establish that ATF-7 and PMK-1 physically interact. Immunoprecipitation using the T7 antibody, followed by immunoblotting using anti-HA, revealed an HA-PMK-1(kinase-dead)-T7-ATF-7 interaction that was dependent on the activated form of PMK-1 |
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Download this section (compressed HTML)Q: What are the specific phosphorylation sites on ATF-7 that are modified by PMK-1, and how do they affect ATF-7's switch from repressor to activator?
Q: Does ATF-7 form heterodimers with other bZIP transcription factors, and how does dimerization affect target gene specificity?
Q: What is the mechanism by which ATF-7 represses transcription in its unphosphorylated state - does it recruit corepressors or block activator access?
Experiment: Mass spectrometry analysis of ATF-7 phosphorylation sites in wild-type vs pmk-1 mutant backgrounds, with and without pathogen exposure. This would identify specific PMK-1-dependent phosphorylation sites and enable structure-function analysis of the repressor-to-activator switch.
Hypothesis: Specific phosphorylation sites on ATF-7 control its switch from repressor to activator
Experiment: Co-IP/mass spectrometry to identify ATF-7 dimerization partners and transcriptional co-regulators in different conditions. This would reveal how ATF-7 achieves target gene specificity and functional diversity in immune vs stress responses.
Hypothesis: ATF-7 dimerization partners and co-regulators determine target gene specificity
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