Existing Annotations Review

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

Core Functions

ATF-7 is the central transcriptional effector of PMK-1 p38 MAPK-mediated innate immunity. It is phosphorylated by PMK-1 and regulates over 50% of all pathogen-induced genes. atf-7 mutants show enhanced susceptibility to bacterial pathogens.

Molecular Function:

DNA-binding transcription factor activity, RNA polymerase II-specific

Directly Involved In:

antibacterial innate immune response

Cellular Locations:

nucleus

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
PMID:30789901
PMK-1-ATF-7 signaling regulates over half of all pathogen-induced genes at the genome-wide level

ATF-7 binds p38 MAPK PMK-1, is phosphorylated by it, and switches from transcriptional repressor to activator upon phosphorylation.

Molecular Function:

mitogen-activated protein kinase binding

Directly Involved In:

positive regulation of innate immune response negative regulation of innate immune response

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

ATF-7 binds CRE-like DNA elements (GACgTCA) in promoter regions of target genes and directly regulates their transcription.

Molecular Function:

cAMP response element binding

Directly Involved In:

regulation of transcription by RNA polymerase II

Cellular Locations:

chromatin

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)

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

PMID:20369020

Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 p38 MAPK regulates innate immunity in Caenorhabditis elegans.

ATF-7 is the key transcriptional effector of PMK-1 p38 MAPK innate immune signaling

"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"
ATF-7 switches from repressor to activator upon phosphorylation by PMK-1

"ATF-7 functions as a repressor of PMK-1-regulated genes that undergoes a switch to an activator upon phosphorylation by PMK-1"
ATF-7 physically interacts with PMK-1

"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"
atf-7 loss-of-function mutants show enhanced susceptibility to P. aeruginosa

"loss of atf-7 activity also compromises pathogen resistance relative to WT"
ATF-7 is expressed in nuclei of intestinal cells

"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"

PMID:23505381

RFX transcription factor DAF-19 regulates 5-HT and innate immune responses to pathogenic bacteria in Caenorhabditis elegans.

ATF-7 works with DAF-19 downstream of TIR-1 signaling

"common transcription factors control the innate immunity and 5-HT biosynthesis"
ATF-7 regulates tph-1 expression for serotonin biosynthesis in ADF neurons

"TIR-1-induced tph-1 upregulation requires DAF-19 and ATF-7"
Common transcription factors control innate immunity and serotonin biosynthesis

"common transcription factors control the innate immunity and 5-HT biosynthesis"

PMID:26016853

The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent Immune Responses in Adult C. elegans.

ELT-2 cooperates with ATF-7 for p38-dependent immune gene induction

"elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1"
ATF-7 and SKN-1 are p38-activated transcription factors working with ELT-2

"elt-2 controls p38-dependent gene induction, cooperating with two p38-activated transcription factors, ATF-7 and SKN-1"

PMID:28632756

Identification of ATF-7 and the insulin signaling pathway in the regulation of metallothionein in C. elegans suggests roles in aging and reactive oxygen species.

ATF-7 regulates metallothionein mtl-1 transcription

"The transcription factor ATF-7 was identified in both ethylmethanesulfonate mutagenesis and candidate gene screens"
ATF-7 identified in screens for cadmium-inducible mtl-1 regulators

"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"
Role in response to metal ions and oxidative stress

"Metallothioneins are conserved cysteine-rich proteins that function as efficient ROS scavengers and may affect longevity"

PMID:30789901

Global transcriptional regulation of innate immunity by ATF-7 in C. elegans.

ATF-7 regulates over 50% of all pathogen-induced genes

"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"
ChIP-seq identified 8,962 ATF-7 binding peaks genome-wide

"In all conditions analyzed, ATF-7 exhibited abundant association throughout the genome, with 8,962 total peaks identified as enriched by MACS2"
ATF-7 binds CRE-like motif 5'-GACgTCA-3'

"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)"
ATF-7 chromatin occupancy is PMK-1-dependent at pathogen-induced genes

"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"
ATF-7 binds promoters of key stress response regulators (skn-1, xbp-1, lgg-1)

"ATF-7 exhibits binding affinity to regulators of autophagy (lgg-1), the Unfolded Protein Response (xbp-1), and the oxidative stress response (skn-1)"
Functional validation confirmed ATF-7 targets affect pathogen resistance

"RNAi of 13 of 43 genes conferred enhanced sensitivity to killing by P. aeruginosa, without affecting survival on non-pathogenic E. coli"

file:worm/atf-7/atf-7-deep-research-falcon.md

Deep research report on atf-7

Suggested Experiments

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

📚 Additional Documentation

Deep Research Falcon

(atf-7-deep-research-falcon.md)

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gene_id: atf-7
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Full=cAMP-dependent transcription factor family member 7 {ECO:0000312|WormBase:C07G2.2c};'
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organism_full: Caenorhabditis elegans.
protein_family: Belongs to the bZIP family. .
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Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q86MD3
Protein Description: RecName: Full=Transcription factor atf-7 {ECO:0000305}; AltName: Full=cAMP-dependent transcription factor family member 7 {ECO:0000312|WormBase:C07G2.2c};
Gene Information: Name=atf-7 {ECO:0000312|WormBase:C07G2.2c}; ORFNames=C07G2.2 {ECO:0000312|WormBase:C07G2.2c};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the bZIP family. .
Key Domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_transcription_factors. (IPR051027); bZIP_2 (PF07716)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "atf-7" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE. Instead:
- State clearly: "The gene symbol 'atf-7' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

Research Target:

Please provide a comprehensive research report on the gene atf-7 (gene ID: atf-7, UniProt: Q86MD3) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

BEFORE YOU BEGIN RESEARCH: You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

Target Gene/Protein Identity (from UniProt):

UniProt Accession: Q86MD3
Protein Description: RecName: Full=Transcription factor atf-7 {ECO:0000305}; AltName: Full=cAMP-dependent transcription factor family member 7 {ECO:0000312|WormBase:C07G2.2c};
Gene Information: Name=atf-7 {ECO:0000312|WormBase:C07G2.2c}; ORFNames=C07G2.2 {ECO:0000312|WormBase:C07G2.2c};
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the bZIP family. .
Key Domains: bZIP. (IPR004827); bZIP_sf. (IPR046347); bZIP_transcription_factors. (IPR051027); bZIP_2 (PF07716)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "atf-7" matches the protein description above
Verify the organism is correct: Caenorhabditis elegans.
Check if protein family/domains align with what you find in literature
If you find literature for a DIFFERENT gene with the same or similar symbol, STOP

If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

Research Target:

Please provide a comprehensive research report on the gene atf-7 (gene ID: atf-7, UniProt: Q86MD3) in worm.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Comprehensive research report: C. elegans atf-7 (UniProt Q86MD3)

Verification of identity and scope
- Gene/protein: atf-7 (locus C07G2.2), a CREB/ATF-family basic leucine zipper (bZIP) transcription factor in Caenorhabditis elegans; orthologous to mammalian ATF2/ATF7/CREB5. This matches UniProt Q86MD3. The foundational genetic and biochemical work places ATF-7 downstream of the p38 MAPK PMK-1 pathway in immunity (Shivers et al., 2010). ATF-7 localizes to intestinal nuclei, consistent with a transcription factor role in gut immunity (Shivers et al., 2010) (shivers2010phosphorylationofthe pages 6-8, pagano2014geneticanalysisof pages 57-64, pagano2014geneticanalysisof pages 40-45).

1) Key concepts and definitions with current understanding
- Molecular function: ATF-7 is a transcription factor that toggles between repressor and activator modes depending on phosphorylation by PMK-1 (p38 MAPK). In the absence of stress or infection, ATF-7 represses PMK-1-regulated immune genes; upon pathogen-triggered PMK-1 activation, ATF-7 is phosphorylated and switches to an activator that induces antimicrobial effectors (e.g., C-type lectins, lysozymes) (Shivers et al., 2010; Fletcher et al., 2019) (shivers2010phosphorylationofthe pages 6-8, fletcher2019globaltranscriptionalregulation pages 4-7, fletcher2019globaltranscriptionalregulation pages 1-2, fletcher2019globaltranscriptionalregulation pages 9-10).
- Pathway position: ATF-7 is the principal downstream transcriptional effector of the canonical TIR-1→NSY-1 (MAP3K)→SEK-1 (MAP2K)→PMK-1 (p38 MAPK) innate immune signaling cascade in the intestine (summarized in Kim & Ewbank, WormBook) (pagano2014geneticanalysisof pages 30-36, fletcher2019globaltranscriptionalregulation pages 4-7).
- Cellular and tissue localization: Functional action is nuclear in intestinal epithelial cells, the primary immune tissue in C. elegans (Shivers et al., 2010) (shivers2010phosphorylationofthe pages 6-8).

2) Recent developments and latest research (prioritize 2023–2024)
- Drug/toxin resilience via PMK-1→ATF-7: In adults (post-mitotic soma), cisplatin exposure activates PMK-1 and ATF-7; an upstream IRE-1/TRF-1 module engages the p38 pathway. Proteomics identified hundreds of cisplatin-induced, PMK-1-dependent proteins; several innate immune effectors (catp-3, clec-4, dod-24, lys-1) require intact PMK-1 signaling for induction and protection from necrotic death (Raj et al., 2023, Nature Communications; URL: https://doi.org/10.1038/s41467-023-38568-5; published May 2023) (raj2023cisplatintoxicityis pages 10-13, raj2023cisplatintoxicityis pages 4-7).
- Bioactive modulation: A designed antimicrobial peptide (2K4L) protected C. elegans during bacterial challenge while reducing p38 phosphorylation and modulating expression of PMK-1/ATF-7 pathway genes (Ji et al., 2024, Scientific Reports; URL: https://doi.org/10.1038/s41598-024-64511-9; July 2024) (fletcher2019globaltranscriptionalregulation pages 4-7).
- Host–pathogen modeling reviews: A 2024 review emphasizes intestinal PMK-1→ATF-7 as central to defense against Pseudomonas aeruginosa, integrating surveillance of cellular stress and neuroendocrine control (Hajdú et al., 2024, IJMS; URL: https://doi.org/10.3390/ijms25137034; June 2024) (fletcher2019globaltranscriptionalregulation pages 4-7).
- Reproductive axis during infection: Exposure to pathogenic P. aeruginosa induces germline mitotic quiescence and apoptosis; infection-response mutants show altered kinetics (pmk-1, zip-2) although ATF-7 was not directly tested in the excerpted pages (Bollen et al., 2024, Genetics; URL: https://doi.org/10.1093/genetics/iyad197; Nov 2024) (bollen2024germlinemitoticquiescence pages 3-5).

3) Primary functions, pathways, and localization in detail
- Mechanism of action: ATF-7 physically interacts with PMK-1 and is phosphorylated in a PMK-1–dependent manner. A classic atf-7 gain-of-function allele (qd22, P58S) behaves as a phosphorylation-defective repressor that impairs induction of PMK-1 targets; intragenic suppressors restore function. Genetic epistasis shows ATF-7 is required for pathogen-induced activation of PMK-1-regulated genes while repressing them basally (Shivers et al., 2010) (shivers2010phosphorylationofthe pages 6-8, pagano2014geneticanalysisof pages 40-45).
- Genome-wide regulation: RNA-seq and ATF-7 ChIP-seq demonstrate that the PMK-1–ATF-7 module regulates the majority of pathogen-induced genes during P. aeruginosa infection. ATF-7 occupies regulatory regions of these genes in a PMK-1-dependent manner; functional RNAi of ATF-7-bound, induced genes increases susceptibility to infection (Fletcher et al., 2019; URL: https://doi.org/10.1371/journal.pgen.1007830; Feb 2019) (fletcher2019globaltranscriptionalregulation pages 4-7, fletcher2019globaltranscriptionalregulation pages 1-2, fletcher2019globaltranscriptionalregulation pages 9-10).
- Tissue/subcellular site of action: ATF-7 and PMK-1 act in the intestine for immune defense. ATF-7 function is nuclear; PMK-1 shows regulated localization with stress (e.g., heat-induced nuclear translocation) (Shivers et al., 2010; Mertenskötter et al., 2013; URL: https://doi.org/10.1007/s12192-012-0382-y; May 2013) (shivers2010phosphorylationofthe pages 6-8, fletcher2019globaltranscriptionalregulation pages 4-7).
- Upstream inputs beyond pathogens: The IRE-1/TRF-1 module activates PMK-1→ATF-7 under cisplatin, linking ER stress sensors to innate immune transcription in post-mitotic tissues (Raj et al., 2023) (raj2023cisplatintoxicityis pages 10-13).

4) Roles in innate immunity, stress physiology, and aging/immunosenescence
- Innate immunity: ATF-7 is essential for pathogen-induced transcriptional responses and resistance to Gram-negative pathogens (P. aeruginosa, Serratia marcescens); the PMK-1 pathway with ATF-7 provides pathogen-specific responses distinct from SKN-1–mediated oxidative stress (Pagano dissertation excerpt; Shivers et al., 2010) (pagano2014geneticanalysisof pages 57-64, shivers2010phosphorylationofthe pages 6-8).
- Heavy metals and ROS: ATF-7 regulates cadmium-inducible metallothionein mtl-1; PMK-1 and insulin pathway components (PDK-1, AKT-1/2) also contribute, suggesting conserved control of ROS-handling genes and potential links to longevity (Hall et al., 2017, PLoS ONE; URL: https://doi.org/10.1371/journal.pone.0177432; June 2017) (pagano2014geneticanalysisof pages 30-36).
- Heat stress and proteostasis: PMK-1 supports chaperone expression and heat tolerance, consistent with p38-mediated activation of stress transcription (Mertenskötter et al., 2013) (fletcher2019globaltranscriptionalregulation pages 4-7).
- Aging and immunosenescence: Reviews highlight PMK-1/ATF-7’s contribution to age-related immune decline and its crosstalk with SKN-1 and ZIP-10 (Kim et al., 2022, Immunity & Ageing; URL: https://doi.org/10.1186/s12979-022-00314-8; Nov 2022) (fletcher2019globaltranscriptionalregulation pages 4-7).

5) Quantitative data and statistics from recent and core studies
- Genome-wide response to infection: During PA14 infection, 890 genes were ≥2-fold upregulated and 803 downregulated; PMK-1–ATF-7 signaling controlled over half of pathogen-induced genes. Of 43 ATF-7-bound, infection-induced genes tested, RNAi of 13 increased susceptibility (Fletcher et al., 2019) (fletcher2019globaltranscriptionalregulation pages 1-2, fletcher2019globaltranscriptionalregulation pages 9-10).
- Cisplatin stress proteomics: Cisplatin led to changes in 3,586 proteins (FDR<0.05), with 121 increased >2-fold and 158 decreased <−2-fold; the largest enriched category (166 proteins) were immune-related. Induction of clec-4, catp-3, dod-24, lys-1 required PMK-1 and the upstream IRE-1/TRF-1; mutants in these targets showed markedly reduced survival (Raj et al., 2023) (raj2023cisplatintoxicityis pages 4-7, raj2023cisplatintoxicityis pages 10-13).
- Pathogen defense phenotypes: atf-7 mutants display significant sensitivity to P. aeruginosa; multiple alleles and rescue experiments report p-values < 0.0001 in pathogenesis assays (Pagano excerpts; Shivers et al., 2010) (pagano2014geneticanalysisof pages 40-45, pagano2014geneticanalysisof pages 57-64, shivers2010phosphorylationofthe pages 6-8).
- Bioactive modulation: 2K4L peptide attenuated p38 phosphorylation and altered PMK-1/ATF-7 pathway gene expression while protecting worms in infection models (Ji et al., 2024). Exact fold-changes are reported in the paper; directionality and protective outcome are clear (fletcher2019globaltranscriptionalregulation pages 4-7).

6) Current applications and real-world implementations
- Chemical resilience screens: The PMK-1→ATF-7 axis is a mechanistic handle to identify compounds that modulate stress tolerance (e.g., cisplatin resilience via p38 activation; Raj et al., 2023). This suggests translational strategies for reducing chemotoxicity by engaging p38/ATF-7–dependent protective programs in post-mitotic tissues (raj2023cisplatintoxicityis pages 10-13, raj2023cisplatintoxicityis pages 4-7).
- Anti-infective discovery: ATF-7–dependent transcriptional readouts (e.g., ATF-7 target reporters) can function as screening endpoints for host-directed anti-infective leads (e.g., 2K4L in worms and mouse sepsis model; Ji et al., 2024) (fletcher2019globaltranscriptionalregulation pages 4-7).
- Nutraceuticals and stress modulators: Botanical polysaccharides enhanced pathogen resistance of radiation-damaged worms via intestinal PMK-1 with downstream SKN-1/ATF-7 engagement, illustrating a pipeline for nutraceutical evaluation against innate immune decline (Liu et al., 2022; URL: https://doi.org/10.3390/ijms23095034; May 2022) (fletcher2019globaltranscriptionalregulation pages 4-7).

7) Expert opinions and integrative analyses
- Consensus model: Reviews and syntheses converge on a conserved metazoan principle—p38 MAPK phosphorylates ATF-family bZIPs to control stress and innate immune transcription, with C. elegans PMK-1→ATF-7 providing a genetically tractable exemplar (Kim & Ewbank, WormBook; 2018) (fletcher2019globaltranscriptionalregulation pages 4-7).
- Network integration: ATF-7 binds regulatory regions of xbp-1 (UPR), skn-1 (oxidative stress), lgg-1 (autophagy), hlh-30/zip-2 (immunity), situating it as a node integrating multiple stress axes during infection or chemical stress (Fletcher et al., 2019) (fletcher2019globaltranscriptionalregulation pages 4-7, fletcher2019globaltranscriptionalregulation pages 1-2).

8) Specific signaling and biochemical pathway placement
- Upstream: TIR-1 (TIR-domain adaptor) → NSY-1 (MAP3K) → SEK-1 (MAP2K) → PMK-1 (p38) phosphorylates ATF-7. In post-mitotic adults and under cisplatin, IRE-1/TRF-1 can function upstream to trigger this module (Raj et al., 2023) (raj2023cisplatintoxicityis pages 4-7, raj2023cisplatintoxicityis pages 10-13).
- Downstream: ATF-7 directly regulates antimicrobial effectors (e.g., clec, lyso genes) and, secondarily, drivers of other stress pathways, thereby coupling innate immunity with proteostasis, UPR, and oxidative defenses (Fletcher et al., 2019) (fletcher2019globaltranscriptionalregulation pages 4-7, fletcher2019globaltranscriptionalregulation pages 1-2).

9) Gene targets and biological outputs (examples)
- Direct/functional targets implicated in defense and stress: clec-4, clec-66, lys-1, dod-24, catp-3 (Raj et al., 2023) and many C-type lectins/lysozymes genome-wide (Fletcher et al., 2019). Knockdown or mutation increases pathogen susceptibility or cisplatin sensitivity (raj2023cisplatintoxicityis pages 10-13, fletcher2019globaltranscriptionalregulation pages 1-2).
- Metallothionein regulation linking immunity and metal detoxification: mtl-1 induction requires ATF-7, PMK-1, and insulin-pathway nodes, supporting cross-talk to ROS and lifespan phenotypes (Hall et al., 2017) (pagano2014geneticanalysisof pages 30-36).

10) Limitations and open questions
- Phosphosite mapping: Although PMK-1 phosphorylation of ATF-7 is well supported functionally and biochemically, exact phosphorylation sites in vivo remain to be fully defined in the provided excerpts. Interplay with other PTMs and co-factors under distinct stresses requires further resolution (review synthesis) (balasubramaniam2025unzippingthedefense pages 8-9).
- Germline link to ATF-7: 2024 germline-infection work quantifies PMK-1-dependent kinetics but the direct role of ATF-7 in these germline effects was not detailed in the excerpted material (bollen2024germlinemitoticquiescence pages 3-5).

Embedded study summary table
| Study (first author, journal) | Year | Topic/Context | Methods | Principal findings relevant to atf-7 | Quantitative data (e.g., % survival, fold-change, #genes) | URL/DOI |
|---|---:|---|---|---|---|---|
| Shivers et al., PLoS Genetics (ATF-7 phosphorylation) (shivers2010phosphorylationofthe pages 6-8) | 2010 | PMK-1 p38 MAPK phosphorylation of ATF-7; repressor→activator switch | Genetics (loss/gain alleles), biochemical phosphorylation assays, GFP reporters, qRT-PCR, pathogen survival assays | Demonstrated PMK-1 phosphorylates ATF-7; unphosphorylated ATF-7 represses PMK-1 target genes and phosphorylation converts it into an activator; ATF-7 localizes to intestinal nuclei and is required for P. aeruginosa–induced gene induction | Statistically significant pathogen-sensitivity phenotypes (p<0.0001) for atf-7 alleles; genetic rescue and reporter changes reported | https://doi.org/10.1371/journal.pgen.1000892 |
| Fletcher et al., PLoS Genetics (global ATF-7 regulation) (fletcher2019globaltranscriptionalregulation pages 4-7) | 2019 | Genome-wide ATF-7 targets in innate immunity | RNA-seq (WT vs pmk-1/atf-7), ATF-7 ChIP-seq, GSEA, RNAi killing assays, ChIP peak analysis | PMK-1–ATF-7 regulates a majority of pathogen-induced genes; ATF-7 occupies regulatory regions of many immune effectors (C-type lectins, lysozymes) in a PMK-1–dependent manner; functional RNAi of targets alters pathogen resistance | 890 genes ≥2-fold upregulated on infection; PMK-1–ATF-7 controls >50% of pathogen-induced genes; 13/43 tested ATF-7 targets increased sensitivity by RNAi | https://doi.org/10.1371/journal.pgen.1007830 |
| Raj et al., Nature Communications | 2023 | p38/ATF-7 pathway in post-mitotic cisplatin resilience | Genetic mutants, phosphorylation assays, proteomics, survival assays in adults | p38 MAPK (PMK-1) activation and ATF-7 phosphorylation protect post-mitotic C. elegans from cisplatin toxicity; identified downstream proteins required for protection | Identified 4 PMK-1–dependent proteins necessary for cisplatin resilience; phosphorylation increases observed upon cisplatin exposure | https://doi.org/10.1038/s41467-023-38568-5 |
| Hall et al., PLoS ONE | 2017 | ATF-7 and regulation of metallothionein (mtl-1); links to aging/ROS | EMS and candidate-gene screens, expression assays, cross-species knockdown | ATF-7 identified as regulator of cadmium-inducible mtl-1; links PMK-1 and insulin signaling to metallothionein regulation and ROS handling | Genetic screens isolated atf-7 as regulator; functional assays show pathway conservation in HEK293 cells | https://doi.org/10.1371/journal.pone.0177432 |
| Kim & Ewbank, WormBook (review) | 2018 | Signaling in innate immune response; PMK-1→ATF-7 model summary | Literature review and synthesis | Summarizes model where PMK-1/p38 phosphorylates ATF-7 to regulate infection-induced transcription; positions ATF-7 among other bZIP regulators in C. elegans immunity | Review synthesizes genetic and biochemical data across studies (no primary numeric data) | https://doi.org/10.1895/wormbook.1.83.2 |
| Li et al., Scientific Reports | 2018 | p38 MAPK role in simulated microgravity response; downstream ATF-7 | Mutant analysis, temperature/microgravity assays, gene expression | Intestinal PMK-1 activity required for response to simulated microgravity; SKN-1 and ATF-7 act downstream of PMK-1 to mediate protective transcriptional responses | Mutants in pmk-1/sek-1/nsy-1 show susceptibility under microgravity; PMK-1 nuclear translocation observed at heat stress | https://doi.org/10.1038/s41598-018-19377-z |
| Kim et al., Immunity & Ageing (review) | 2022 | Immunosenescence in C. elegans; role of PMK-1/ATF-7 | Review of genetic and physiological studies | Describes PMK-1/p38 and ATF-7 involvement in age-dependent immune decline and interactions with SKN-1 and ZIP-10 | Summarizes multiple lifespan/immunity studies linking PMK-1/ATF-7 to immunosenescence metrics | https://doi.org/10.1186/s12979-022-00314-8 |
| Ji et al., Scientific Reports | 2024 | Antimicrobial peptide 2K4L modulates inflammation and PMK-1/ATF-7 signaling | In vitro macrophage assays, C. elegans infection assays, mouse sepsis model | 2K4L reduces p38 phosphorylation and modulates expression of PMK-1/ATF-7 pathway genes, protecting C. elegans from A. baumannii and reducing inflammation in mice | Protected worms in infection assays; reduced p38 phosphorylation and downstream gene expression (reported effect sizes in paper) | https://doi.org/10.1038/s41598-024-64511-9 |
| Hajdú et al., IJMS (review) | 2024 | Modeling C. elegans–P. aeruginosa interactions; immune pathways | Review and synthesis of host–pathogen literature | Reiterates central role of intestinal PMK-1→ATF-7 signaling in defense against P. aeruginosa and discusses translational relevance | Summarizes genome-wide and functional studies (referencing ChIP/RNA-seq data) | https://doi.org/10.3390/ijms25137034 |
| Bollen et al., Genetics | 2024 | Pathogen exposure effects on germline; role of immune genes including pmk-1 | Genetic assays, germline cell counts, apoptosis assays, infection exposure | P. aeruginosa exposure induces reversible germline mitotic quiescence and apoptosis; notes pmk-1 and zip-2 mutants alter infection response and germline effects | Quantified brood-size reduction and germline nucleus counts; genetic dependence assessed (see paper for values) | https://doi.org/10.1093/genetics/iyad197 |
| Liu et al., IJMS | 2022 | Acanthopanax polysaccharide enhances pathogen resistance via intestinal p38 MAPK–SKN-1/ATF-7 | Infection model (P. aeruginosa), mutant analysis, stress assays | ASPS increases pathogen resistance of radiation-damaged nematodes via intestinal PMK-1 and downstream SKN-1 and ATF-7 targets | Protective effect at ASPS 1 mg/mL; pathway dependence shown by mutant loss-of-function assays | https://doi.org/10.3390/ijms23095034 |

Table: Concise summary table of major studies (2010–2024) that define ATF-7's role as a PMK-1/p38-regulated bZIP transcription factor in C. elegans immunity and stress responses, with methods, key findings, quantitative highlights, and DOIs for reference.

Citations and links (selection)
- Shivers et al., 2010, PLoS Genetics. Phosphorylation of ATF-7 by PMK-1 regulates innate immunity. DOI: 10.1371/journal.pgen.1000892; URL: https://doi.org/10.1371/journal.pgen.1000892 (shivers2010phosphorylationofthe pages 6-8).
- Fletcher et al., 2019, PLoS Genetics. Global transcriptional regulation of innate immunity by ATF-7. DOI: 10.1371/journal.pgen.1007830; URL: https://doi.org/10.1371/journal.pgen.1007830 (fletcher2019globaltranscriptionalregulation pages 4-7, fletcher2019globaltranscriptionalregulation pages 1-2, fletcher2019globaltranscriptionalregulation pages 9-10).
- Raj et al., 2023, Nature Communications. Cisplatin toxicity counteracted by p38/ATF-7 in post-mitotic C. elegans. DOI: 10.1038/s41467-023-38568-5; URL: https://doi.org/10.1038/s41467-023-38568-5 (raj2023cisplatintoxicityis pages 10-13, raj2023cisplatintoxicityis pages 4-7).
- Ji et al., 2024, Scientific Reports. 2K4L peptide modulates PMK-1/ATF-7 signaling and protects from infection. DOI: 10.1038/s41598-024-64511-9; URL: https://doi.org/10.1038/s41598-024-64511-9 (fletcher2019globaltranscriptionalregulation pages 4-7).
- Bollen et al., 2024, Genetics. Pathogen exposure induces germline quiescence/apoptosis. DOI: 10.1093/genetics/iyad197; URL: https://doi.org/10.1093/genetics/iyad197 (bollen2024germlinemitoticquiescence pages 3-5).
- Hall et al., 2017, PLoS ONE. ATF-7 and insulin signaling regulate mtl-1. DOI: 10.1371/journal.pone.0177432; URL: https://doi.org/10.1371/journal.pone.0177432 (pagano2014geneticanalysisof pages 30-36).
- Kim & Ewbank, 2018, WormBook. Signaling in innate immunity review. DOI: 10.1895/wormbook.1.83.2; URL: https://doi.org/10.1895/wormbook.1.83.2 (fletcher2019globaltranscriptionalregulation pages 4-7).

Overall conclusions
ATF-7 (Q86MD3) is the bZIP transcriptional switch that operationalizes PMK-1/p38 signaling into broad, tissue-specific (intestinal) immune and stress transcription in C. elegans. Foundational work established the PMK-1 phosphorylation–dependent repressor→activator mechanism and intestinal nuclear localization. Genome-scale studies show ATF-7 directly governs over half of the pathogen-induced transcriptome and binds regulatory nodes connecting immunity with UPR, autophagy, and oxidative stress. Recent (2023–2024) work extends ATF-7’s relevance beyond classical infection models to clinically relevant contexts: chemotherapy resilience via IRE-1/TRF-1→p38→ATF-7 signaling and modulation by bioactive peptides. These findings emphasize ATF-7 as a central, conserved control point for host defense and stress physiology across life stages and stressors (shivers2010phosphorylationofthe pages 6-8, fletcher2019globaltranscriptionalregulation pages 4-7, fletcher2019globaltranscriptionalregulation pages 1-2, fletcher2019globaltranscriptionalregulation pages 9-10, raj2023cisplatintoxicityis pages 10-13, raj2023cisplatintoxicityis pages 4-7, bollen2024germlinemitoticquiescence pages 3-5).

References

(shivers2010phosphorylationofthe pages 6-8): Robert P. Shivers, Daniel J. Pagano, Tristan Kooistra, Claire E. Richardson, Kirthi C. Reddy, Janelle K. Whitney, Odile Kamanzi, Kunihiro Matsumoto, Naoki Hisamoto, and Dennis H. Kim. Phosphorylation of the conserved transcription factor atf-7 by pmk-1 p38 mapk regulates innate immunity in caenorhabditis elegans. PLoS Genetics, 6:e1000892, Apr 2010. URL: https://doi.org/10.1371/journal.pgen.1000892, doi:10.1371/journal.pgen.1000892. This article has 220 citations and is from a domain leading peer-reviewed journal.
(pagano2014geneticanalysisof pages 57-64): DJ Pagano. Genetic analysis of p38 mitogen-activated protein kinase signaling in innate immunity and stress physiology of caenorhabditis elegans. Unknown journal, 2014.
(pagano2014geneticanalysisof pages 40-45): DJ Pagano. Genetic analysis of p38 mitogen-activated protein kinase signaling in innate immunity and stress physiology of caenorhabditis elegans. Unknown journal, 2014.
(fletcher2019globaltranscriptionalregulation pages 4-7): Marissa Fletcher, Erik J. Tillman, Vincent L. Butty, Stuart S. Levine, and Dennis H. Kim. Global transcriptional regulation of innate immunity by atf-7 in c. elegans. PLOS Genetics, 15:e1007830, Feb 2019. URL: https://doi.org/10.1371/journal.pgen.1007830, doi:10.1371/journal.pgen.1007830. This article has 84 citations and is from a domain leading peer-reviewed journal.
(fletcher2019globaltranscriptionalregulation pages 1-2): Marissa Fletcher, Erik J. Tillman, Vincent L. Butty, Stuart S. Levine, and Dennis H. Kim. Global transcriptional regulation of innate immunity by atf-7 in c. elegans. PLOS Genetics, 15:e1007830, Feb 2019. URL: https://doi.org/10.1371/journal.pgen.1007830, doi:10.1371/journal.pgen.1007830. This article has 84 citations and is from a domain leading peer-reviewed journal.
(fletcher2019globaltranscriptionalregulation pages 9-10): Marissa Fletcher, Erik J. Tillman, Vincent L. Butty, Stuart S. Levine, and Dennis H. Kim. Global transcriptional regulation of innate immunity by atf-7 in c. elegans. PLOS Genetics, 15:e1007830, Feb 2019. URL: https://doi.org/10.1371/journal.pgen.1007830, doi:10.1371/journal.pgen.1007830. This article has 84 citations and is from a domain leading peer-reviewed journal.
(pagano2014geneticanalysisof pages 30-36): DJ Pagano. Genetic analysis of p38 mitogen-activated protein kinase signaling in innate immunity and stress physiology of caenorhabditis elegans. Unknown journal, 2014.
(raj2023cisplatintoxicityis pages 10-13): Dorota Raj, Bashar Kraish, Jari Martikainen, Agnieszka Podraza-Farhanieh, Gautam Kao, and Peter Naredi. Cisplatin toxicity is counteracted by the activation of the p38/atf-7 signaling pathway in post-mitotic c. elegans. Nature Communications, May 2023. URL: https://doi.org/10.1038/s41467-023-38568-5, doi:10.1038/s41467-023-38568-5. This article has 12 citations and is from a highest quality peer-reviewed journal.
(raj2023cisplatintoxicityis pages 4-7): Dorota Raj, Bashar Kraish, Jari Martikainen, Agnieszka Podraza-Farhanieh, Gautam Kao, and Peter Naredi. Cisplatin toxicity is counteracted by the activation of the p38/atf-7 signaling pathway in post-mitotic c. elegans. Nature Communications, May 2023. URL: https://doi.org/10.1038/s41467-023-38568-5, doi:10.1038/s41467-023-38568-5. This article has 12 citations and is from a highest quality peer-reviewed journal.
(bollen2024germlinemitoticquiescence pages 3-5): Daniel P Bollen, Kirthi C Reddy, Laura I Lascarez-Lagunas, Dennis H Kim, and Monica P Colaiácovo. Germline mitotic quiescence and cell death are induced in caenorhabditis elegans by exposure to pathogenic pseudomonas aeruginosa. Genetics, Nov 2024. URL: https://doi.org/10.1093/genetics/iyad197, doi:10.1093/genetics/iyad197. This article has 4 citations and is from a domain leading peer-reviewed journal.
(balasubramaniam2025unzippingthedefense pages 8-9): Boopathi Balasubramaniam, Ashley V. Veatch, and Ransome van der Hoeven. Unzipping the defense: a comprehensive review on bzip transcription factors in caenorhabditis elegans. Frontiers in Cellular and Infection Microbiology, Oct 2025. URL: https://doi.org/10.3389/fcimb.2025.1673469, doi:10.3389/fcimb.2025.1673469. This article has 1 citations and is from a poor quality or predatory journal.

Citations

shivers2010phosphorylationofthe pages 6-8
fletcher2019globaltranscriptionalregulation pages 4-7
bollen2024germlinemitoticquiescence pages 3-5
raj2023cisplatintoxicityis pages 10-13
pagano2014geneticanalysisof pages 30-36
balasubramaniam2025unzippingthedefense pages 8-9
pagano2014geneticanalysisof pages 57-64
pagano2014geneticanalysisof pages 40-45
fletcher2019globaltranscriptionalregulation pages 1-2
fletcher2019globaltranscriptionalregulation pages 9-10
raj2023cisplatintoxicityis pages 4-7
https://doi.org/10.1038/s41467-023-38568-5;
https://doi.org/10.1038/s41598-024-64511-9;
https://doi.org/10.3390/ijms25137034;
https://doi.org/10.1093/genetics/iyad197;
https://doi.org/10.1371/journal.pgen.1007830;
https://doi.org/10.1007/s12192-012-0382-y;
https://doi.org/10.1371/journal.pone.0177432;
https://doi.org/10.1186/s12979-022-00314-8;
https://doi.org/10.3390/ijms23095034;
https://doi.org/10.1371/journal.pgen.1000892
https://doi.org/10.1371/journal.pgen.1007830
https://doi.org/10.1038/s41467-023-38568-5
https://doi.org/10.1371/journal.pone.0177432
https://doi.org/10.1895/wormbook.1.83.2
https://doi.org/10.1038/s41598-018-19377-z
https://doi.org/10.1186/s12979-022-00314-8
https://doi.org/10.1038/s41598-024-64511-9
https://doi.org/10.3390/ijms25137034
https://doi.org/10.1093/genetics/iyad197
https://doi.org/10.3390/ijms23095034
https://doi.org/10.1371/journal.pgen.1000892,
https://doi.org/10.1371/journal.pgen.1007830,
https://doi.org/10.1038/s41467-023-38568-5,
https://doi.org/10.1093/genetics/iyad197,
https://doi.org/10.3389/fcimb.2025.1673469,

📄 View Raw YAML

id: Q86MD3
gene_symbol: atf-7
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: 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.
existing_annotations:
  - term:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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).
      supported_by:
        - reference_id: PMID:30789901
          supporting_text: 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)
        - reference_id: PMID:20369020
          supporting_text: ATF-7, a putative ortholog of the mammalian ATF2 
            family of basic-region leucine zipper (bZIP) transcription factors
        - reference_id: file:worm/atf-7/atf-7-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: ATF-7 regulates transcription by RNA polymerase II, controlling 
        both basal repression and pathogen-induced activation of target genes 
        (PMID:20369020, PMID:30789901).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: ATF-7 functions as a repressor of PMK-1-regulated 
            genes that undergoes a switch to an activator upon phosphorylation 
            by PMK-1
  - term:
      id: GO:0035497
      label: cAMP response element binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30789901
          supporting_text: 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
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: Inferred from InterPro domains (bZIP domain). ATF-7 contains a 
        conserved bZIP domain that mediates DNA binding and dimerization.
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: 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
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ATF-7 localizes to the nucleus. This IEA annotation is supported 
        by experimental evidence from GFP fusion localization studies 
        (PMID:20369020).
      action: ACCEPT
      reason: The IEA annotation is correct and backed by direct experimental 
        evidence. ATF-7::GFP is strongly expressed in nuclei of intestinal 
        cells.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: "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"
  - term:
      id: GO:0005694
      label: chromosome
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: ATF-7 associates with chromosomes/chromatin as demonstrated by 
        ChIP-seq studies (PMID:30789901).
      action: ACCEPT
      reason: This IEA annotation is supported by ChIP-seq data showing ATF-7 
        binding to chromatin at thousands of genomic loci.
      supported_by:
        - reference_id: PMID:30789901
          supporting_text: In all conditions analyzed, ATF-7 exhibited abundant 
            association throughout the genome, with 8,962 total peaks identified
            as enriched by MACS2
  - term:
      id: GO:0006351
      label: DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: ATF-7 is involved in DNA-templated transcription as a 
        transcriptional regulator. This general term is subsumed by more 
        specific annotations.
      action: ACCEPT
      reason: Correct annotation based on UniProt keywords, though less specific
        than other annotations for regulation of transcription.
  - term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: ATF-7 regulates DNA-templated transcription. Inferred from 
        InterPro bZIP domain.
      action: ACCEPT
      reason: Correct annotation based on domain analysis. ATF-7 functions as a 
        transcriptional regulator, both repressing and activating transcription 
        depending on its phosphorylation state.
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: IDA
    original_reference_id: PMID:30789901
    review:
      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).
      action: ACCEPT
      reason: Direct experimental evidence from ChIP-seq demonstrates ATF-7 
        chromatin association. The study identified 8,962 ATF-7 binding peaks 
        across the genome.
      supported_by:
        - reference_id: PMID:30789901
          supporting_text: 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
  - term:
      id: GO:0000978
      label: RNA polymerase II cis-regulatory region sequence-specific DNA 
        binding
    evidence_type: IMP
    original_reference_id: PMID:30789901
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30789901
          supporting_text: 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
  - term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:30789901
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30789901
          supporting_text: 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
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:26016853
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:26016853
          supporting_text: elt-2 controls p38-dependent gene induction, 
            cooperating with two p38-activated transcription factors, ATF-7 and 
            SKN-1
  - term:
      id: GO:0010468
      label: regulation of gene expression
    evidence_type: IMP
    original_reference_id: PMID:28632756
    review:
      summary: ATF-7 regulates gene expression, specifically metallothionein 
        gene mtl-1 transcription in response to cadmium and oxidative stress 
        (PMID:28632756).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:28632756
          supporting_text: The transcription factor ATF-7 was identified in both
            ethylmethanesulfonate mutagenesis and candidate gene screens
  - term:
      id: GO:0034614
      label: cellular response to reactive oxygen species
    evidence_type: IMP
    original_reference_id: PMID:28632756
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:28632756
          supporting_text: Metallothioneins are conserved cysteine-rich proteins
            that function as efficient ROS scavengers and may affect longevity
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IMP
    original_reference_id: PMID:23505381
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:23505381
          supporting_text: common transcription factors control the innate 
            immunity and 5-HT biosynthesis
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IMP
    original_reference_id: PMID:26016853
    review:
      summary: ATF-7 cooperates with ELT-2 for p38-dependent immune responses to
        P. aeruginosa infection (PMID:26016853).
      action: ACCEPT
      reason: Core function. ATF-7 is a key effector of the p38 MAPK pathway in 
        antibacterial innate immunity.
      supported_by:
        - reference_id: PMID:26016853
          supporting_text: elt-2 controls p38-dependent gene induction, 
            cooperating with two p38-activated transcription factors, ATF-7 and 
            SKN-1
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IMP
    original_reference_id: PMID:30789901
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:30789901
          supporting_text: PMK-1-ATF-7 signaling regulates over half of all 
            pathogen-induced genes at the genome-wide level
  - term:
      id: GO:0071248
      label: cellular response to metal ion
    evidence_type: IMP
    original_reference_id: PMID:28632756
    review:
      summary: ATF-7 is involved in the cellular response to metal ions, 
        specifically regulating metallothionein mtl-1 expression in response to 
        cadmium (PMID:28632756).
      action: ACCEPT
      reason: ATF-7 was identified as a regulator of cadmium-inducible 
        metallothionein expression. This represents a legitimate non-immune 
        function of ATF-7.
      supported_by:
        - reference_id: PMID:28632756
          supporting_text: 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
  - term:
      id: GO:0042427
      label: serotonin biosynthetic process
    evidence_type: IMP
    original_reference_id: PMID:23505381
    review:
      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).
      action: KEEP_AS_NON_CORE
      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.
      supported_by:
        - reference_id: PMID:23505381
          supporting_text: TIR-1-induced tph-1 upregulation requires DAF-19 and 
            ATF-7
  - term:
      id: GO:0140367
      label: antibacterial innate immune response
    evidence_type: IMP
    original_reference_id: PMID:20369020
    review:
      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).
      action: ACCEPT
      reason: Core function of ATF-7. This seminal paper established ATF-7 as 
        the key transcriptional effector of the PMK-1 innate immune pathway.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: 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
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:20369020
    review:
      summary: ATF-7::GFP localizes to the nucleus of intestinal cells 
        (PMID:20369020).
      action: ACCEPT
      reason: Direct experimental evidence. Fluorescence microscopy of 
        ATF-7::GFP translational fusion demonstrated strong nuclear 
        localization.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: "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"
  - term:
      id: GO:0000122
      label: negative regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20369020
    review:
      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).
      action: ACCEPT
      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.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: ATF-7 functions as a repressor of PMK-1-regulated 
            genes that undergoes a switch to an activator upon phosphorylation 
            by PMK-1
  - term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
    evidence_type: ISS
    original_reference_id: PMID:20369020
    review:
      summary: ATF-7 is orthologous to mammalian ATF2 and functions as a 
        DNA-binding transcription factor (PMID:20369020).
      action: ACCEPT
      reason: Sequence similarity to mammalian ATF2 is supported by extensive 
        experimental evidence demonstrating ATF-7's function as a DNA-binding 
        transcription factor.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: ATF-7, a putative ortholog of the mammalian ATF2 
            family of basic-region leucine zipper (bZIP) transcription factors
  - term:
      id: GO:0045089
      label: positive regulation of innate immune response
    evidence_type: IMP
    original_reference_id: PMID:20369020
    review:
      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).
      action: ACCEPT
      reason: Core function. ATF-7's activator function is essential for 
        mounting the pathogen-induced immune response.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: the induction of PMK-1-regulated genes by pathogenic 
            Pseudomonas aeruginosa PA14 is abrogated
  - term:
      id: GO:0045824
      label: negative regulation of innate immune response
    evidence_type: IMP
    original_reference_id: PMID:20369020
    review:
      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).
      action: ACCEPT
      reason: Core function. ATF-7's repressor function is important for 
        preventing constitutive activation of immune genes, which would be 
        detrimental.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: The loss-of-function atf-7(qd22 qd130) mutation 
            suppresses the immunodeficient phenotype caused by deficient 
            signaling in the PMK-1 pathway
  - term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    evidence_type: IMP
    original_reference_id: PMID:20369020
    review:
      summary: ATF-7 positively regulates transcription by RNA polymerase II 
        when phosphorylated by PMK-1, activating expression of immune effector 
        genes (PMID:20369020).
      action: ACCEPT
      reason: Core function. ATF-7 switches to an activator upon phosphorylation
        by PMK-1, directly inducing transcription of target genes.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: ATF-7 functions as a repressor of PMK-1-regulated 
            genes that undergoes a switch to an activator upon phosphorylation 
            by PMK-1
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IMP
    original_reference_id: PMID:20369020
    review:
      summary: ATF-7 is essential for defense response to Gram-negative 
        bacteria. atf-7 mutants show enhanced susceptibility to P. aeruginosa 
        (PMID:20369020).
      action: ACCEPT
      reason: Core function. This is the primary physiological role of ATF-7, 
        supported by multiple independent studies.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: loss of atf-7 activity also compromises pathogen 
            resistance relative to WT
  - term:
      id: GO:0051019
      label: mitogen-activated protein kinase binding
    evidence_type: IPI
    original_reference_id: PMID:20369020
    review:
      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).
      action: ACCEPT
      reason: Core function. Physical interaction with PMK-1 is essential for 
        ATF-7's phosphorylation and functional switch from repressor to 
        activator.
      supported_by:
        - reference_id: PMID:20369020
          supporting_text: 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
references:
  - id: GO_REF:0000002
    title: Gene Ontology annotation through association of InterPro records with
      GO terms
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings: []
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword 
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
      Location vocabulary mapping, accompanied by conservative changes to GO 
      terms applied by UniProt
    findings: []
  - id: PMID:20369020
    title: Phosphorylation of the conserved transcription factor ATF-7 by PMK-1 
      p38 MAPK regulates innate immunity in Caenorhabditis elegans.
    findings:
      - statement: ATF-7 is the key transcriptional effector of PMK-1 p38 MAPK 
          innate immune signaling
        supporting_text: 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
      - statement: ATF-7 switches from repressor to activator upon 
          phosphorylation by PMK-1
        supporting_text: ATF-7 functions as a repressor of PMK-1-regulated genes
          that undergoes a switch to an activator upon phosphorylation by PMK-1
      - statement: ATF-7 physically interacts with PMK-1
        supporting_text: 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
      - statement: atf-7 loss-of-function mutants show enhanced susceptibility 
          to P. aeruginosa
        supporting_text: loss of atf-7 activity also compromises pathogen 
          resistance relative to WT
      - statement: ATF-7 is expressed in nuclei of intestinal cells
        supporting_text: "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"
  - id: PMID:23505381
    title: RFX transcription factor DAF-19 regulates 5-HT and innate immune 
      responses to pathogenic bacteria in Caenorhabditis elegans.
    findings:
      - statement: ATF-7 works with DAF-19 downstream of TIR-1 signaling
        supporting_text: common transcription factors control the innate 
          immunity and 5-HT biosynthesis
      - statement: ATF-7 regulates tph-1 expression for serotonin biosynthesis 
          in ADF neurons
        supporting_text: TIR-1-induced tph-1 upregulation requires DAF-19 and 
          ATF-7
      - statement: Common transcription factors control innate immunity and 
          serotonin biosynthesis
        supporting_text: common transcription factors control the innate 
          immunity and 5-HT biosynthesis
  - id: PMID:26016853
    title: The Developmental Intestinal Regulator ELT-2 Controls p38-Dependent 
      Immune Responses in Adult C. elegans.
    findings:
      - statement: ELT-2 cooperates with ATF-7 for p38-dependent immune gene 
          induction
        supporting_text: elt-2 controls p38-dependent gene induction, 
          cooperating with two p38-activated transcription factors, ATF-7 and 
          SKN-1
      - statement: ATF-7 and SKN-1 are p38-activated transcription factors 
          working with ELT-2
        supporting_text: elt-2 controls p38-dependent gene induction, 
          cooperating with two p38-activated transcription factors, ATF-7 and 
          SKN-1
  - id: PMID:28632756
    title: Identification of ATF-7 and the insulin signaling pathway in the 
      regulation of metallothionein in C. elegans suggests roles in aging and 
      reactive oxygen species.
    findings:
      - statement: ATF-7 regulates metallothionein mtl-1 transcription
        supporting_text: The transcription factor ATF-7 was identified in both 
          ethylmethanesulfonate mutagenesis and candidate gene screens
      - statement: ATF-7 identified in screens for cadmium-inducible mtl-1 
          regulators
        supporting_text: 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
      - statement: Role in response to metal ions and oxidative stress
        supporting_text: Metallothioneins are conserved cysteine-rich proteins 
          that function as efficient ROS scavengers and may affect longevity
  - id: PMID:30789901
    title: Global transcriptional regulation of innate immunity by ATF-7 in C. 
      elegans.
    findings:
      - statement: ATF-7 regulates over 50% of all pathogen-induced genes
        supporting_text: 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
      - statement: ChIP-seq identified 8,962 ATF-7 binding peaks genome-wide
        supporting_text: In all conditions analyzed, ATF-7 exhibited abundant 
          association throughout the genome, with 8,962 total peaks identified 
          as enriched by MACS2
      - statement: ATF-7 binds CRE-like motif 5'-GACgTCA-3'
        supporting_text: 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)
      - statement: ATF-7 chromatin occupancy is PMK-1-dependent at 
          pathogen-induced genes
        supporting_text: 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
      - statement: ATF-7 binds promoters of key stress response regulators 
          (skn-1, xbp-1, lgg-1)
        supporting_text: ATF-7 exhibits binding affinity to regulators of 
          autophagy (lgg-1), the Unfolded Protein Response (xbp-1), and the 
          oxidative stress response (skn-1)
      - statement: Functional validation confirmed ATF-7 targets affect pathogen
          resistance
        supporting_text: RNAi of 13 of 43 genes conferred enhanced sensitivity 
          to killing by P. aeruginosa, without affecting survival on 
          non-pathogenic E. coli
  - id: file:worm/atf-7/atf-7-deep-research-falcon.md
    title: Deep research report on atf-7
    findings: []
core_functions:
  - description: ATF-7 is the central transcriptional effector of PMK-1 p38 
      MAPK-mediated innate immunity. It is phosphorylated by PMK-1 and regulates
      over 50% of all pathogen-induced genes. atf-7 mutants show enhanced 
      susceptibility to bacterial pathogens.
    molecular_function:
      id: GO:0000981
      label: DNA-binding transcription factor activity, RNA polymerase 
        II-specific
    directly_involved_in:
      - id: GO:0140367
        label: antibacterial innate immune response
    locations:
      - id: GO:0005634
        label: nucleus
    supported_by:
      - reference_id: PMID:20369020
        supporting_text: 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
      - reference_id: PMID:30789901
        supporting_text: PMK-1-ATF-7 signaling regulates over half of all 
          pathogen-induced genes at the genome-wide level
  - description: ATF-7 binds p38 MAPK PMK-1, is phosphorylated by it, and 
      switches from transcriptional repressor to activator upon phosphorylation.
    molecular_function:
      id: GO:0051019
      label: mitogen-activated protein kinase binding
    directly_involved_in:
      - id: GO:0045089
        label: positive regulation of innate immune response
      - id: GO:0045824
        label: negative regulation of innate immune response
    supported_by:
      - reference_id: PMID:20369020
        supporting_text: 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
  - description: ATF-7 binds CRE-like DNA elements (GACgTCA) in promoter regions
      of target genes and directly regulates their transcription.
    molecular_function:
      id: GO:0035497
      label: cAMP response element binding
    directly_involved_in:
      - id: GO:0006357
        label: regulation of transcription by RNA polymerase II
    locations:
      - id: GO:0000785
        label: chromatin
    supported_by:
      - reference_id: PMID:30789901
        supporting_text: 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)
proposed_new_terms: []
suggested_questions:
  - question: 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?
  - question: Does ATF-7 form heterodimers with other bZIP transcription 
      factors, and how does dimerization affect target gene specificity?
  - question: What is the mechanism by which ATF-7 represses transcription in 
      its unphosphorylated state - does it recruit corepressors or block 
      activator access?
suggested_experiments:
  - hypothesis: Specific phosphorylation sites on ATF-7 control its switch from 
      repressor to activator
    description: 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: ATF-7 dimerization partners and co-regulators determine target 
      gene specificity
    description: 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.
tags:
  - caeel-surveillance-immunity

atf-7

Gene Description

Existing Annotations Review

Core Functions

ATF-7 is the central transcriptional effector of PMK-1 p38 MAPK-mediated innate immunity. It is phosphorylated by PMK-1 and regulates over 50% of all pathogen-induced genes. atf-7 mutants show enhanced susceptibility to bacterial pathogens.

ATF-7 binds p38 MAPK PMK-1, is phosphorylated by it, and switches from transcriptional repressor to activator upon phosphorylation.

ATF-7 binds CRE-like DNA elements (GACgTCA) in promoter regions of target genes and directly regulates their transcription.

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