Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0140367 antibacterial innate immune response	IEP PMID:20133860 bZIP transcription factor zip-2 mediates an early response t...	ACCEPT	Summary: IEP (inferred from expression pattern) annotation: irg-2 is a member of the "infection response gene" class defined by Estes et al. 2010 as genes specifically induced by virulent P. aeruginosa but not by an attenuated gacA mutant. Troemel et al. 2006 independently place irg-2 (as C49G7.5) among the top P. aeruginosa-induced genes at 4 h. The evidence is transcriptional induction during bacterial infection, which the IEP code accurately reflects. Reason: The annotation correctly captures irg-2's defining, well-replicated property — strong and specific transcriptional induction during antibacterial (P. aeruginosa) infection — and the IEP evidence code is appropriate for an expression-based inference. Retained as a core aspect of the gene. Note the boundary of this evidence: it demonstrates induction, not that the IRG-2 protein is functionally required for the response (see knowledge_gaps). Supporting Evidence: PMID:20133860 We focused on genes that are induced in C. elegans by infection with the bacterial pathogen Pseudomonas aeruginosa, but are not induced by an isogenic attenuated gacA mutant. PMID:17096597 We tested induction of the top five genes upregulated by P. aeruginosa versus E. coli at 4 h
GO:0003674 molecular_function	ND GO_REF:0000015	ACCEPT	Summary: ND (no data) annotation at the molecular_function root: no molecular function has been experimentally determined for IRG-2. The protein has no recognizable catalytic domain or characterized motif, and — unlike its co-regulated paralog irg-1 (which carries a predicted NADAR/YbiA-like domain) — offers no sequence feature from which to even hypothesize an activity. Reason: The ND annotation honestly reflects the current state of knowledge: IRG-2 is molecular-function dark. This is a genuine biology knowledge gap (see knowledge_gaps), not a curation defect to be repaired by asserting an unsupported activity.
GO:0050829 defense response to Gram-negative bacterium	IEP PMID:20133860 bZIP transcription factor zip-2 mediates an early response t...	ACCEPT	Summary: IEP annotation specifying that irg-2's induction occurs in response to a Gram-negative bacterium. P. aeruginosa, the pathogen that induces irg-2, is Gram-negative, so this is a more specific and appropriate child of the antibacterial response term, supported by the same expression evidence. Reason: Accurate and appropriately specific: irg-2 is induced by the Gram-negative pathogen P. aeruginosa, and the IEP evidence code matches the expression-based source. As with the other IEP term, this reflects induction rather than a demonstrated protein-level effector requirement. Supporting Evidence: PMID:20133860 This screen identified zip-2, a bZIP transcription factor that is required for inducing irg-1, as well as several other genes, and is important for defense against infection by P. aeruginosa.
GO:0045087 innate immune response	HEP PMID:16968778 A conserved role for a GATA transcription factor in regulati...	ACCEPT	Summary: HEP (inferred from high-throughput expression pattern) annotation from the Shapira et al. 2006 genome-wide study of intestinal infection responses, in which the endodermal GATA factor ELT-2 governs a suite of P. aeruginosa-induced genes. This is a broader parent of the antibacterial-response terms and provides independent high-throughput expression support that irg-2 is part of the intestinal innate immune transcriptional program. Reason: Valid and appropriate. C. elegans has only innate immunity, so this general term correctly classifies irg-2's immune involvement, and the HEP evidence code matches the high-throughput expression source. It is retained as a higher-level classification alongside the more specific antibacterial terms. Supporting Evidence: PMID:16968778 Gene expression and functional RNAi-based analyses identified the tissue-specific GATA transcription factor ELT-2 as a major regulator of an early intestinal protective response to infection with the human bacterial pathogen Pseudomonas aeruginosa.

Core Functions

irg-2 acts as a downstream transcriptional effector of the ZIP-2 branch of C. elegans surveillance immunity. Its mRNA is a specific, PMK-1-independent readout of the intestinal antibacterial defense response, induced when virulent P. aeruginosa (or other insults that block host translation) is detected. Its role is defined by this regulated expression; the biochemical activity of the IRG-2 protein and whether it is itself required for pathogen resistance remain undetermined.

Directly Involved In:

antibacterial innate immune response defense response to Gram-negative bacterium

Supporting Evidence:

PMID:20133860
We focused on genes that are induced in C. elegans by infection with the bacterial pathogen Pseudomonas aeruginosa, but are not induced by an isogenic attenuated gacA mutant.
PMID:32350153
the expression of the ZIP-2 targets irg-1 (Figure 2A) and irg-2 (Figure 2B) increased 24.0-fold and 15.5-fold, respectively, from day 1 to day 8 of adulthood

References

GO_REF:0000015

Use of the ND evidence code for Gene Ontology (GO) terms

Standard GO reference for No Data (ND) annotations, used when no experimental or computational evidence is available for a given aspect of gene function. Applied here to the molecular_function root for irg-2.

PMID:20133860

bZIP transcription factor zip-2 mediates an early response to Pseudomonas aeruginosa infection in Caenorhabditis elegans.

Defines the "infection response gene" (irg) class as genes specifically induced by virulent P. aeruginosa but not by an attenuated gacA mutant; irg-2 is a member of this class.

"We focused on genes that are induced in C. elegans by infection with the bacterial pathogen Pseudomonas aeruginosa, but are not induced by an isogenic attenuated gacA mutant."
The bZIP transcription factor ZIP-2 is required for inducing irg-1 and several other infection-response genes and is important for defense against P. aeruginosa.

"This screen identified zip-2, a bZIP transcription factor that is required for inducing irg-1, as well as several other genes, and is important for defense against infection by P. aeruginosa."

PMID:17096597

p38 MAPK regulates expression of immune response genes and contributes to longevity in C. elegans.

irg-2 (C49G7.5) is among the top P. aeruginosa-induced genes and is induced via a PMK-1 (p38 MAPK)-independent pathway.

"The remaining two genes (C49G7.5 and F53E10.4) must therefore be induced via a PMK-1–independent pathway"

PMID:22520465

C. elegans detects pathogen-induced translational inhibition to activate immune signaling.

The zip-2/irg surveillance pathway is activated by pathogen-induced inhibition of host mRNA translation, sensed via endocytosed Exotoxin A, which raises ZIP-2 protein levels.

"P. aeruginosa infection inhibits mRNA translation in the intestine via the endocytosed translation inhibitor Exotoxin A, which leads to an increase in ZIP-2 protein levels."
The zip-2/irg-1 pathway is also induced by disruption of core host processes including translational inhibition, independent of infection.

"In the absence of infection we find that the zip-2/irg-1 pathway is upregulated following disruption of several core host processes, including inhibition of mRNA translation."

PMID:32350153

A cellular surveillance and defense system that delays aging phenotypes in C. elegans.

irg-2 is a bona fide ZIP-2 target whose expression rises strongly with age; the age-dependent increase is largely ZIP-2-dependent.

"the expression of the ZIP-2 targets irg-1 (Figure 2A) and irg-2 (Figure 2B) increased 24.0-fold and 15.5-fold, respectively, from day 1 to day 8 of adulthood"
The age-dependent increases in irg-1 and irg-2 depend on ZIP-2.

"indicating that the age-dependent increases in irg-1 and irg-2 expression were largely dependent on ZIP-2."

PMID:16968778

A conserved role for a GATA transcription factor in regulating epithelial innate immune responses.

Genome-wide study identifying the endodermal GATA factor ELT-2 as a major regulator of the intestinal infection-response transcriptional program that includes irg-2.

"Gene expression and functional RNAi-based analyses identified the tissue-specific GATA transcription factor ELT-2 as a major regulator of an early intestinal protective response to infection with the human bacterial pathogen Pseudomonas aeruginosa."

Suggested Experiments

Experiment: Generate an irg-2 deletion (and irg-1;irg-2 double) and assay survival and intestinal bacterial burden on P. aeruginosa PA14 versus control bacteria, with transgenic rescue, to test whether IRG-2 protein is required for defense.

Hypothesis: IRG-2 is a functional effector required for wild-type resistance to P. aeruginosa, not merely a downstream reporter.

Experiment: Express and purify recombinant IRG-2 and screen for candidate biochemical activities and for direct antibacterial activity against P. aeruginosa in vitro; determine its structure (experimental or from AlphaFold) to search for cryptic active-site or fold features.

Hypothesis: IRG-2 possesses a discrete molecular activity (enzymatic or antimicrobial) that its lack of an annotated domain has obscured.

Experiment: Use endogenous fluorescent tagging plus affinity/proximity proteomics (AP-MS) of IRG-2 in infected animals to determine subcellular localization and physical interaction partners.

Hypothesis: IRG-2 localizes to a defined compartment (e.g. secretory/apical intestinal) and acts through specific protein partners.

Knowledge Gaps

What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).

Gap: The molecular function of IRG-2 is undetermined. No catalytic, binding, or antimicrobial activity has been demonstrated, no physical interaction partner is known, and — unlike its co-regulated paralog irg-1, which carries a predicted NADAR/YbiA-like domain — the protein has no recognizable domain from which to even hypothesize an activity.

OPEN BIOLOGY MF_DARK

What is known: irg-2 is a well-established transcriptional readout of the ZIP-2 surveillance-immunity pathway: strongly and specifically induced by virulent P. aeruginosa (PMID:20133860), by translational inhibition (Exotoxin A / cycloheximide; PMID:22520465), and with age in a ZIP-2-dependent manner (PMID:32350153), independent of PMK-1 p38 MAPK (PMID:17096597). The 278-aa protein has only a short disordered/polar-residue region and no catalytic motif, and evidence exists solely at the transcript level (UniProt PE=2).

Significance: irg-2 is one of the canonical downstream effectors invoked to define the ZIP-2 arm of C. elegans surveillance immunity, yet what its protein product actually does — enzyme, antimicrobial effector, or inert reporter — is entirely unknown, leaving the effector output of this well-studied pathway mechanistically blank.

What would resolve it: Recombinant-protein biochemistry and/or structure determination to test for an enzymatic or antimicrobial activity; affinity/proximity proteomics (AP-MS) or yeast two-hybrid to identify partners; endogenous tagging for subcellular localization.

Provenance (the field's own admissions):

"GO:0003674 molecular_function molecular_function ECO:0000307 ND" — file:worm/irg-2/irg-2-goa.tsv
"No enzymatic activity has been assigned to the protein." — file:worm/irg-2/irg-2-deep-research-falcon.md
"the expression of the ZIP-2 targets irg-1 (Figure 2A) and irg-2 (Figure 2B)" — PMID:32350153

Gap: It is unknown whether the IRG-2 protein is functionally required for defense against P. aeruginosa. All evidence linking irg-2 to immunity is transcriptional (IEP/HEP); no irg-2 loss-of-function survival, colonization, or immune phenotype has been reported, so whether IRG-2 is a causal effector or a passive reporter of ZIP-2 activation is unresolved.

OPEN BIOLOGY

What is known: The regulator ZIP-2 is required for defense against P. aeruginosa (PMID:20133860), and irg-2 is a ZIP-2-dependent target (PMID:32350153); but requirement of the regulator does not establish requirement of this particular target. irg-2's association with defense rests entirely on expression correlation, not on perturbation of irg-2 itself.

Significance: Distinguishing effector from reporter is essential before irg-2 can be assigned a causal role in innate immunity, and would clarify whether the ZIP-2 pathway's protective output runs through irg-2 or through other, as-yet-unidentified effectors.

What would resolve it: Loss-of-function (deletion/RNAi) and overexpression of irg-2 with quantitative survival and bacterial-burden assays on P. aeruginosa PA14, ideally with rescue, to test whether IRG-2 protein is required for or sufficient to enhance resistance.

Provenance (the field's own admissions):

"is important for defense against infection by P. aeruginosa." — PMID:20133860

Deep Research

Falcon

(irg-2-deep-research-falcon.md)

Comprehensive Research Report: *irg-2* (Infection Response Gene 2, C49G7.5) in *Caenorhabditis elegans* Falcon Edison Scientific Literature 39 citations 1 artifacts 2026-07-03T20:36:38.824210

Edison artifact artifact-00 (text/markdown)

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.

Comprehensive Research Report: irg-2 (Infection Response Gene 2, C49G7.5) in Caenorhabditis elegans

1. Gene Identity and Overview

The gene irg-2 (ORF name C49G7.5; UniProt accession O16224) encodes Infection Response Protein 2 in Caenorhabditis elegans. It was originally identified as one of the most strongly pathogen-induced genes in genome-wide transcriptomic analyses of C. elegans exposed to the human pathogen Pseudomonas aeruginosa (troemel2006p38mapkregulates pages 8-9, troemel2006p38mapkregulates pages 7-8). The gene is classified as an immunity-linked gene (ILG), a group first named based on their upregulation following pathogen challenge (fanelli2023immunitylinkedgenesare pages 1-2). irg-2 belongs to the core host immune response gene set in C. elegans and is induced by exposure to diverse bacterial and fungal pathogens (simonsen2012strengthinnumbers pages 5-6).

2. Transcriptional Regulation and Signaling Pathway Context

2.1 PMK-1-Independent Induction (Class D Pathogen Response Gene)

A seminal study by Troemel et al. (2006) classified pathogen-responsive genes into five classes (A–E) based on their dependence on the PMK-1 p38 MAPK pathway for basal and induced expression. irg-2/C49G7.5 was designated a Class D gene, meaning it is induced by P. aeruginosa infection but does not require PMK-1 for either its basal expression on E. coli or its induction upon pathogen exposure (troemel2006p38mapkregulates pages 8-9, troemel2006p38mapkregulates pages 7-8). This classification indicated early on that irg-2 is regulated by an alternative, PMK-1-independent immune signaling mechanism. Approximately 75% of P. aeruginosa-induced genes were found to be independent of PMK-1, pointing to the existence of additional immune pathways (troemel2006p38mapkregulates pages 9-11, troemel2006p38mapkregulates pages 7-8).

2.2 ZIP-2 bZIP Transcription Factor Pathway

The PMK-1-independent pathway regulating irg-2 was subsequently identified as the ZIP-2 pathway. ZIP-2 is a bZIP transcription factor that, together with its heterodimeric partner CEBP-2, activates transcription of immune effector genes including irg-1 and irg-2 in the intestine (vasquezrifo2020pseudomonasaeruginosacleaves pages 7-9, kniazeva2025translationelongationdefects pages 1-2). ZIP-2 functions as a sensor of translational elongation defects — a form of surveillance immunity. When pathogens such as P. aeruginosa deploy ribosome-targeting toxins (e.g., exotoxin A), host translational elongation is inhibited, triggering a +1 frameshift in the zip-2 mRNA that converts an upstream overlapping open reading frame (oORF) into a functional bZIP transcription factor (kniazeva2025translationelongationdefects pages 3-5, kniazeva2025translationelongationdefects pages 5-6). This mechanism enables rapid, transcription-independent immune activation; the zip-2 mRNA is already transcribed and being translated, so the frameshift produces the functional protein without the delays of new transcription, splicing, or ribosome recruitment (kniazeva2025translationelongationdefects pages 1-2).

irg-2 is strongly induced (over 100-fold) by P. aeruginosa carrying exotoxin A and by various translational elongation inhibitors including hygromycin B, anisomycin, blasticidin S, and fusidic acid (kniazeva2025translationelongationdefects pages 2-3, kniazeva2025translationelongationdefects pages 1-2). This induction requires ZIP-2, as it is abolished by zip-2 mutation or RNAi knockdown (kniazeva2025translationelongationdefects pages 1-2). The ZIP-2 pathway functions independently of the PMK-1/p38 MAPK pathway, consistent with the Class D designation of irg-2 (afridi2025therolesof pages 6-7).

2.3 TGF-β/DBL-1 Signaling Pathway

irg-2 expression is also regulated by the TGF-β signaling pathway in C. elegans, mediated by the ligand DBL-1, the receptors DAF-4/SMA-6, and downstream SMAD transcription factors. This positions irg-2 within the broader core host immune response that includes C-type lectins and other immune effectors (simonsen2012strengthinnumbers pages 5-6).

2.4 ARF-1 GTPase and Golgi Membrane Stress Pathway

A 2023 study by Fanelli et al. demonstrated that irg-2 is robustly activated when Golgi function is disrupted through knockdown of the ADP-ribosylation factor arf-1 or the coatomer component copa-1 (fanelli2023immunitylinkedgenesare pages 7-9, fanelli2023immunitylinkedgenesare pages 5-7). This activation occurs independently of direct pathogen exposure and is linked to changes in phosphatidylcholine (PC) levels in secretory organelle membranes. Low PC limits ARF-1 function at the Golgi, providing a mechanistic link between lipid metabolism perturbations and ILG activation (fanelli2023immunitylinkedgenesare pages 5-7, fanelli2023immunitylinkedgenesare pages 1-2). This finding helps explain the longstanding observation that ILGs are upregulated both by pathogen attack and by metabolic stress — both converge on disruption of secretory pathway function.

2.5 Oleate Requirement

The monounsaturated fatty acid oleate, synthesized by the stearoyl-CoA desaturases FAT-6 and FAT-7, is required for pathogen-induced induction of irg-2. Anderson et al. (2019) showed that the fold induction of irg-2 during P. aeruginosa infection was significantly attenuated in fat-6(tm331);fat-7(wa36) double-mutant animals compared to wild-type (anderson2019thefattyacid pages 6-8). This requirement is specific to oleate and not downstream polyunsaturated fatty acids.

2.6 Negative Regulation by RNP-6/PUF60

The splicing factor RNP-6 (ortholog of mammalian PUF60) functions as a negative regulator of irg-2 expression. Knockdown of rnp-6 by RNAi significantly elevates irg-2 levels (p<0.0001) under non-infected conditions (kew2020evolutionarilyconservedregulation pages 8-10, kew2020evolutionarilyconservedregulation pages 6-8). RNP-6 suppresses immunity through inhibition of PMK-1 MAPK signaling activity and represents an evolutionarily conserved mechanism balancing immune activation with longevity (kew2020evolutionarilyconservedregulation pages 1-2, kew2020evolutionarilyconservedregulation pages 10-12).

2.7 ENDU-2-Mediated Post-Heat Stress Regulation

irg-2 is classified as a Class III post-heat stress (post-HS) responsive gene, upregulated specifically during the recovery phase after hormetic heat stress rather than during the acute stress itself (xu2023reprogrammingofthe pages 5-6, xu2023reprogrammingofthe pages 3-5). The endoribonuclease ENDU-2 binds directly to the irg-2 promoter and facilitates RNA polymerase II recruitment, promoting irg-2 transcription after heat stress. This involves cooperation with the SWI/SNF chromatin remodeling complex (xu2023reprogrammingofthe pages 7-9, xu2023reprogrammingofthe pages 11-12, xu2023reprogrammingofthe pages 6-7). RNAi knockdown of irg-2 abolished the beneficial effects of hormetic heat stress, including resistance to subsequent heat and cadmium stress (xu2023reprogrammingofthe pages 5-6).

The following table summarizes the key regulatory pathways controlling irg-2:

Pathway/Regulator	Effect on irg-2 Expression	Stimulus/Context	Key Reference
ZIP-2 bZIP transcription factor	Positive regulator; required for induction of irg-2 downstream of translational inhibition	Activated during Pseudomonas aeruginosa infection and by translation-elongation defects/ribosome damage caused by bacterial toxins	Vasquez-Rifo et al. 2020; Kniazeva & Ruvkun 2025 (vasquezrifo2020pseudomonasaeruginosacleaves pages 7-9, kniazeva2025translationelongationdefects pages 1-2, kniazeva2025translationelongationdefects pages 3-5, kniazeva2025translationelongationdefects pages 5-6)
PMK-1 p38 MAPK	Largely independent; irg-2/C49G7.5 is a Class D pathogen-response gene not requiring PMK-1 for induction	P. aeruginosa infection; induced despite PMK-1 loss, indicating alternative immune signaling	Troemel et al. 2006 (troemel2006p38mapkregulates pages 8-9, troemel2006p38mapkregulates pages 7-8)
TGF-β/DBL-1 pathway	Positive regulator of irg-2 as part of core host immune response	Pathogen-responsive immune transcriptional program; linked to DBL-1, DAF-4/SMA-6, and SMAD signaling	Simonsen et al. 2012 review summarizing primary studies (simonsen2012strengthinnumbers pages 5-6)
ENDU-2	Positive regulator; promotes irg-2 transcription by binding its promoter and facilitating Pol II recruitment	Post-heat-stress recovery / heat hormesis; irg-2 is a Class III post-heat-stress responsive gene	Xu et al. 2023 (xu2023reprogrammingofthe pages 7-9, xu2023reprogrammingofthe pages 9-11, xu2023reprogrammingofthe pages 11-12, xu2023reprogrammingofthe pages 5-6, xu2023reprogrammingofthe pages 6-7, xu2023reprogrammingofthe pages 3-5)
RNP-6/PUF60 splicing factor	Negative/suppressive regulator; loss of RNP-6 elevates irg-2 expression	Basal immune homeostasis and infection-responsive splicing/PMK-1-linked immune regulation	Kew et al. 2020 (kew2020evolutionarilyconservedregulation pages 8-10, kew2020evolutionarilyconservedregulation pages 6-8, kew2020evolutionarilyconservedregulation pages 1-2, kew2020evolutionarilyconservedregulation pages 10-12)
Oleate / fat-6 / fat-7	Required for full pathogen-induced irg-2 induction; deficiency attenuates induction	P. aeruginosa infection; oleate biosynthesis supports immune effector induction	Anderson et al. 2019 (anderson2019thefattyacid pages 6-8)
ARF-1 / Golgi membrane stress pathway	irg-2 is activated when ARF-1 or Golgi trafficking is disrupted	Membrane lipid imbalance, compromised Golgi/secretory function, or increased secretory load; arf-1 or copa-1 knockdown robustly activates irg-2	Fanelli et al. 2023 (fanelli2023immunitylinkedgenesare pages 7-9, fanelli2023immunitylinkedgenesare pages 5-7, fanelli2023immunitylinkedgenesare pages 1-2)

Table: This table summarizes the main signaling pathways and cellular stress mechanisms reported to control irg-2 expression in C. elegans. It highlights where evidence supports positive regulation, negative regulation, or pathway independence, which is useful for interpreting irg-2 as an infection- and stress-responsive gene.

3. Tissue Expression and Subcellular Localization

irg-2 is predominantly expressed in the intestine of C. elegans, consistent with the intestine's central role as the primary site of pathogen encounter and innate immune activation in this organism (kim2018signalinginthe pages 14-16, xu2023reprogrammingofthe pages 5-6). The intestinal epithelium is the tissue where P. aeruginosa toxins exert their translational inhibition effects, and where the ZIP-2 surveillance pathway operates (vasquezrifo2020pseudomonasaeruginosacleaves pages 7-9, balasubramaniam2025unzippingthedefense pages 15-16). An irg-2p::mCherry transcriptional reporter has been used to monitor its expression pattern, confirming dominant intestinal expression, particularly among post-heat-stress responsive genes (xu2023reprogrammingofthe pages 5-6).

At the subcellular level, functional studies indicate that IRG-2 protein operates within or in association with the secretory pathway. RNAi knockdown of irg-2 causes increased puncta size and aggregation of secreted GFP reporters (ssGFP) in both body wall muscle cells and intestinal cells, phenocopying the effects of arf-1 RNAi knockdown (fanelli2023immunitylinkedgenesare pages 9-12). These findings suggest that IRG-2 functions at the level of Golgi/ER trafficking and protein secretion.

4. Molecular Function and Protein Characteristics

The precise biochemical function of IRG-2 remains incompletely characterized. Unlike many well-annotated immune effectors in C. elegans (e.g., C-type lectins, CUB-domain proteins, lysozymes, or ShK toxin-like proteins), IRG-2 lacks clearly recognizable domains associated with antimicrobial peptide function. It is categorized in the "STRESS RESPONSE: Pathogen: unassigned" WormCat category (fanelli2023immunitylinkedgenesare pages 13-14). No enzymatic activity has been assigned to the protein.

However, the functional evidence from Fanelli et al. (2023) provides important insight. Rather than acting as a conventional antimicrobial effector that directly kills or neutralizes pathogens, IRG-2 appears to function in supporting and protecting the secretory pathway during conditions of membrane stress or immune activation. When irg-2 is knocked down, secreted protein reporters aggregate and pool abnormally, and the accumulation of a pathogen-responsive CUB-domain fusion protein is disrupted (fanelli2023immunitylinkedgenesare pages 9-12, fanelli2023immunitylinkedgenesare pages 13-14). The authors propose that IRG-2 may function as part of a "multi-membrane" stress response encompassing both the ER and the Golgi in trafficking, helping to counteract stress on secretory function that occurs after both pathogen exposure and broad membrane lipid disruption (fanelli2023immunitylinkedgenesare pages 12-13, fanelli2023immunitylinkedgenesare pages 13-14).

This model is consistent with the observation that pathogen responses depend heavily on ER stress pathways to manage the increased demands of immune protein trafficking and secretion (fanelli2023immunitylinkedgenesare pages 12-13). Thus, IRG-2 may be classified as a secretory pathway support factor that is coordinately upregulated during immune activation to ensure efficient production and delivery of antimicrobial effectors.

5. Induction Specificity

irg-2 expression is induced by live P. aeruginosa (strain PA14) and by the attenuated gacA mutant strain of PA14, but not by dead P. aeruginosa (kim2018signalinginthe pages 51-52, kim2018signalinginthe pages 46-51). This pattern indicates that irg-2 responds to active bacterial factors — likely virulence effectors such as toxins that inhibit translation — rather than to conserved microbial structural components (pathogen-associated molecular patterns). This is consistent with the surveillance immunity model whereby the host detects the effects of pathogen virulence factors (e.g., translational inhibition) rather than the pathogen molecules themselves (vasquezrifo2020pseudomonasaeruginosacleaves pages 7-9, kniazeva2025translationelongationdefects pages 1-2).

6. Broader Biological Roles

6.1 Heat Hormesis and Stress Resistance

Beyond its role in pathogen defense, irg-2 plays a functional role in heat hormesis — the phenomenon whereby brief heat stress during early adulthood extends lifespan and improves stress resistance in C. elegans. As a Class III post-HS gene, irg-2 is essential for the protective effects of hormetic heat stress. Its transcriptional activation after heat stress is mediated by ENDU-2 and requires chromatin remodeling via the SWI/SNF complex (xu2023reprogrammingofthe pages 11-12, xu2023reprogrammingofthe pages 6-7). Failure to induce irg-2 after heat stress eliminates the beneficial hormetic effects (xu2023reprogrammingofthe pages 5-6).

6.2 Integration with Metabolic Regulation

The requirement for oleate in irg-2 induction (anderson2019thefattyacid pages 6-8) and the activation of irg-2 by membrane lipid perturbations affecting Golgi function (fanelli2023immunitylinkedgenesare pages 7-9, fanelli2023immunitylinkedgenesare pages 5-7) place this gene at the intersection of metabolism and immunity — a concept now termed immunometabolism. These connections suggest that irg-2 expression may serve as an integrating readout of both metabolic state and immune challenge.

7. Summary

irg-2 (C49G7.5) encodes a pathogen-responsive, immunity-linked protein in C. elegans that is principally regulated by the ZIP-2 bZIP transcription factor pathway in response to translational elongation defects caused by pathogen-derived toxins. It is induced independently of the canonical PMK-1 p38 MAPK pathway and is additionally regulated by the TGF-β/DBL-1 pathway, the ARF-1/Golgi membrane stress pathway, the ENDU-2-mediated post-heat stress pathway, and is negatively modulated by the splicing factor RNP-6/PUF60. The protein is predominantly expressed in intestinal epithelial cells and functions within the secretory pathway, where it appears to support protein trafficking and secretion during conditions of immune activation or membrane stress. While IRG-2 lacks recognizable antimicrobial domains, its loss compromises secretory function, suggesting it facilitates the efficient delivery of immune effectors during pathogen challenge. Its involvement in both pathogen defense and heat hormesis illustrates the integrated nature of stress and immune responses in C. elegans.

References

(troemel2006p38mapkregulates pages 8-9): Emily R. Troemel, Stephanie W. Chu, Valerie Reinke, Siu Sylvia Lee, Frederick M. Ausubel, and Dennis H. Kim. P38 mapk regulates expression of immune response genes and contributes to longevity in c. elegans. PLoS Genetics, 2:e183, Sep 2006. URL: https://doi.org/10.1371/journal.pgen.0020183, doi:10.1371/journal.pgen.0020183. This article has 831 citations and is from a domain leading peer-reviewed journal.
(troemel2006p38mapkregulates pages 7-8): Emily R. Troemel, Stephanie W. Chu, Valerie Reinke, Siu Sylvia Lee, Frederick M. Ausubel, and Dennis H. Kim. P38 mapk regulates expression of immune response genes and contributes to longevity in c. elegans. PLoS Genetics, 2:e183, Sep 2006. URL: https://doi.org/10.1371/journal.pgen.0020183, doi:10.1371/journal.pgen.0020183. This article has 831 citations and is from a domain leading peer-reviewed journal.
(fanelli2023immunitylinkedgenesare pages 1-2): Matthew J. Fanelli, Christofer M. Welsh, Dominique S. Lui, Lorissa J. Smulan, and Amy K. Walker. Immunity-linked genes are stimulated by a membrane stress pathway linked to golgi function and the arf-1 gtpase. Science Advances, Dec 2023. URL: https://doi.org/10.1126/sciadv.adi5545, doi:10.1126/sciadv.adi5545. This article has 13 citations and is from a highest quality peer-reviewed journal.
(simonsen2012strengthinnumbers pages 5-6): Karina T. Simonsen, Sandra F. Gallego, Nils J. Færgeman, and Birgitte H. Kallipolitis. Strength in numbers. Virulence, 3:477-484, Oct 2012. URL: https://doi.org/10.4161/viru.21906, doi:10.4161/viru.21906. This article has 36 citations and is from a peer-reviewed journal.
(troemel2006p38mapkregulates pages 9-11): Emily R. Troemel, Stephanie W. Chu, Valerie Reinke, Siu Sylvia Lee, Frederick M. Ausubel, and Dennis H. Kim. P38 mapk regulates expression of immune response genes and contributes to longevity in c. elegans. PLoS Genetics, 2:e183, Sep 2006. URL: https://doi.org/10.1371/journal.pgen.0020183, doi:10.1371/journal.pgen.0020183. This article has 831 citations and is from a domain leading peer-reviewed journal.
(vasquezrifo2020pseudomonasaeruginosacleaves pages 7-9): Alejandro Vasquez-Rifo, Emiliano P. Ricci, and Victor Ambros. Pseudomonas aeruginosa cleaves the decoding center of caenorhabditis elegans ribosomes. PLoS Biology, 18:e3000969, Dec 2020. URL: https://doi.org/10.1371/journal.pbio.3000969, doi:10.1371/journal.pbio.3000969. This article has 24 citations and is from a highest quality peer-reviewed journal.
(kniazeva2025translationelongationdefects pages 1-2): Marina Kniazeva and Gary Ruvkun. Translation elongation defects activate the caenorhabditis elegans zip-2 bzip transcription factor–mediated toxin defense. Proceedings of the National Academy of Sciences of the United States of America, Feb 2025. URL: https://doi.org/10.1073/pnas.2423578122, doi:10.1073/pnas.2423578122. This article has 6 citations and is from a highest quality peer-reviewed journal.
(kniazeva2025translationelongationdefects pages 3-5): Marina Kniazeva and Gary Ruvkun. Translation elongation defects activate the caenorhabditis elegans zip-2 bzip transcription factor–mediated toxin defense. Proceedings of the National Academy of Sciences of the United States of America, Feb 2025. URL: https://doi.org/10.1073/pnas.2423578122, doi:10.1073/pnas.2423578122. This article has 6 citations and is from a highest quality peer-reviewed journal.
(kniazeva2025translationelongationdefects pages 5-6): Marina Kniazeva and Gary Ruvkun. Translation elongation defects activate the caenorhabditis elegans zip-2 bzip transcription factor–mediated toxin defense. Proceedings of the National Academy of Sciences of the United States of America, Feb 2025. URL: https://doi.org/10.1073/pnas.2423578122, doi:10.1073/pnas.2423578122. This article has 6 citations and is from a highest quality peer-reviewed journal.
(kniazeva2025translationelongationdefects pages 2-3): Marina Kniazeva and Gary Ruvkun. Translation elongation defects activate the caenorhabditis elegans zip-2 bzip transcription factor–mediated toxin defense. Proceedings of the National Academy of Sciences of the United States of America, Feb 2025. URL: https://doi.org/10.1073/pnas.2423578122, doi:10.1073/pnas.2423578122. This article has 6 citations and is from a highest quality peer-reviewed journal.
(afridi2025therolesof pages 6-7): Muhammad Irfan Afridi and Haijun Tu. The roles of distinct transcriptional factors in the innate immunity of c. elegans. Cells, 14:327, Feb 2025. URL: https://doi.org/10.3390/cells14050327, doi:10.3390/cells14050327. This article has 4 citations.
(fanelli2023immunitylinkedgenesare pages 7-9): Matthew J. Fanelli, Christofer M. Welsh, Dominique S. Lui, Lorissa J. Smulan, and Amy K. Walker. Immunity-linked genes are stimulated by a membrane stress pathway linked to golgi function and the arf-1 gtpase. Science Advances, Dec 2023. URL: https://doi.org/10.1126/sciadv.adi5545, doi:10.1126/sciadv.adi5545. This article has 13 citations and is from a highest quality peer-reviewed journal.
(fanelli2023immunitylinkedgenesare pages 5-7): Matthew J. Fanelli, Christofer M. Welsh, Dominique S. Lui, Lorissa J. Smulan, and Amy K. Walker. Immunity-linked genes are stimulated by a membrane stress pathway linked to golgi function and the arf-1 gtpase. Science Advances, Dec 2023. URL: https://doi.org/10.1126/sciadv.adi5545, doi:10.1126/sciadv.adi5545. This article has 13 citations and is from a highest quality peer-reviewed journal.
(anderson2019thefattyacid pages 6-8): Sarah M. Anderson, Hilary K. Cheesman, Nicholas D. Peterson, J. Elizabeth Salisbury, Alexander A. Soukas, and Read Pukkila-Worley. The fatty acid oleate is required for innate immune activation and pathogen defense in caenorhabditis elegans. PLOS Pathogens, 15:e1007893, Jun 2019. URL: https://doi.org/10.1371/journal.ppat.1007893, doi:10.1371/journal.ppat.1007893. This article has 92 citations and is from a highest quality peer-reviewed journal.
(kew2020evolutionarilyconservedregulation pages 8-10): Chun Kew, Wenming Huang, Julia Fischer, Raja Ganesan, Nirmal Robinson, and Adam Antebi. Evolutionarily conserved regulation of immunity by the splicing factor rnp-6/puf60. eLife, Jun 2020. URL: https://doi.org/10.7554/elife.57591, doi:10.7554/elife.57591. This article has 29 citations and is from a domain leading peer-reviewed journal.
(kew2020evolutionarilyconservedregulation pages 6-8): Chun Kew, Wenming Huang, Julia Fischer, Raja Ganesan, Nirmal Robinson, and Adam Antebi. Evolutionarily conserved regulation of immunity by the splicing factor rnp-6/puf60. eLife, Jun 2020. URL: https://doi.org/10.7554/elife.57591, doi:10.7554/elife.57591. This article has 29 citations and is from a domain leading peer-reviewed journal.
(kew2020evolutionarilyconservedregulation pages 1-2): Chun Kew, Wenming Huang, Julia Fischer, Raja Ganesan, Nirmal Robinson, and Adam Antebi. Evolutionarily conserved regulation of immunity by the splicing factor rnp-6/puf60. eLife, Jun 2020. URL: https://doi.org/10.7554/elife.57591, doi:10.7554/elife.57591. This article has 29 citations and is from a domain leading peer-reviewed journal.
(kew2020evolutionarilyconservedregulation pages 10-12): Chun Kew, Wenming Huang, Julia Fischer, Raja Ganesan, Nirmal Robinson, and Adam Antebi. Evolutionarily conserved regulation of immunity by the splicing factor rnp-6/puf60. eLife, Jun 2020. URL: https://doi.org/10.7554/elife.57591, doi:10.7554/elife.57591. This article has 29 citations and is from a domain leading peer-reviewed journal.
(xu2023reprogrammingofthe pages 5-6): Fan Xu, Ruoyao Li, Erika D. von Gromoff, Friedel Drepper, Bettina Knapp, Bettina Warscheid, Ralf Baumeister, and Wenjing Qi. Reprogramming of the transcriptome after heat stress mediates heat hormesis in caenorhabditis elegans. Nature Communications, Jul 2023. URL: https://doi.org/10.1038/s41467-023-39882-8, doi:10.1038/s41467-023-39882-8. This article has 31 citations and is from a highest quality peer-reviewed journal.
(xu2023reprogrammingofthe pages 3-5): Fan Xu, Ruoyao Li, Erika D. von Gromoff, Friedel Drepper, Bettina Knapp, Bettina Warscheid, Ralf Baumeister, and Wenjing Qi. Reprogramming of the transcriptome after heat stress mediates heat hormesis in caenorhabditis elegans. Nature Communications, Jul 2023. URL: https://doi.org/10.1038/s41467-023-39882-8, doi:10.1038/s41467-023-39882-8. This article has 31 citations and is from a highest quality peer-reviewed journal.
(xu2023reprogrammingofthe pages 7-9): Fan Xu, Ruoyao Li, Erika D. von Gromoff, Friedel Drepper, Bettina Knapp, Bettina Warscheid, Ralf Baumeister, and Wenjing Qi. Reprogramming of the transcriptome after heat stress mediates heat hormesis in caenorhabditis elegans. Nature Communications, Jul 2023. URL: https://doi.org/10.1038/s41467-023-39882-8, doi:10.1038/s41467-023-39882-8. This article has 31 citations and is from a highest quality peer-reviewed journal.
(xu2023reprogrammingofthe pages 11-12): Fan Xu, Ruoyao Li, Erika D. von Gromoff, Friedel Drepper, Bettina Knapp, Bettina Warscheid, Ralf Baumeister, and Wenjing Qi. Reprogramming of the transcriptome after heat stress mediates heat hormesis in caenorhabditis elegans. Nature Communications, Jul 2023. URL: https://doi.org/10.1038/s41467-023-39882-8, doi:10.1038/s41467-023-39882-8. This article has 31 citations and is from a highest quality peer-reviewed journal.
(xu2023reprogrammingofthe pages 6-7): Fan Xu, Ruoyao Li, Erika D. von Gromoff, Friedel Drepper, Bettina Knapp, Bettina Warscheid, Ralf Baumeister, and Wenjing Qi. Reprogramming of the transcriptome after heat stress mediates heat hormesis in caenorhabditis elegans. Nature Communications, Jul 2023. URL: https://doi.org/10.1038/s41467-023-39882-8, doi:10.1038/s41467-023-39882-8. This article has 31 citations and is from a highest quality peer-reviewed journal.
(xu2023reprogrammingofthe pages 9-11): Fan Xu, Ruoyao Li, Erika D. von Gromoff, Friedel Drepper, Bettina Knapp, Bettina Warscheid, Ralf Baumeister, and Wenjing Qi. Reprogramming of the transcriptome after heat stress mediates heat hormesis in caenorhabditis elegans. Nature Communications, Jul 2023. URL: https://doi.org/10.1038/s41467-023-39882-8, doi:10.1038/s41467-023-39882-8. This article has 31 citations and is from a highest quality peer-reviewed journal.
(kim2018signalinginthe pages 14-16): Dennis H. Kim and J. Ewbank. Signaling in the innate immune response. WormBook : the online review of C. elegans biology, 2018:1-35, Aug 2018. URL: https://doi.org/10.1895/wormbook.1.83.2, doi:10.1895/wormbook.1.83.2. This article has 152 citations.
(balasubramaniam2025unzippingthedefense pages 15-16): 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 2 citations.
(fanelli2023immunitylinkedgenesare pages 9-12): Matthew J. Fanelli, Christofer M. Welsh, Dominique S. Lui, Lorissa J. Smulan, and Amy K. Walker. Immunity-linked genes are stimulated by a membrane stress pathway linked to golgi function and the arf-1 gtpase. Science Advances, Dec 2023. URL: https://doi.org/10.1126/sciadv.adi5545, doi:10.1126/sciadv.adi5545. This article has 13 citations and is from a highest quality peer-reviewed journal.
(fanelli2023immunitylinkedgenesare pages 13-14): Matthew J. Fanelli, Christofer M. Welsh, Dominique S. Lui, Lorissa J. Smulan, and Amy K. Walker. Immunity-linked genes are stimulated by a membrane stress pathway linked to golgi function and the arf-1 gtpase. Science Advances, Dec 2023. URL: https://doi.org/10.1126/sciadv.adi5545, doi:10.1126/sciadv.adi5545. This article has 13 citations and is from a highest quality peer-reviewed journal.
(fanelli2023immunitylinkedgenesare pages 12-13): Matthew J. Fanelli, Christofer M. Welsh, Dominique S. Lui, Lorissa J. Smulan, and Amy K. Walker. Immunity-linked genes are stimulated by a membrane stress pathway linked to golgi function and the arf-1 gtpase. Science Advances, Dec 2023. URL: https://doi.org/10.1126/sciadv.adi5545, doi:10.1126/sciadv.adi5545. This article has 13 citations and is from a highest quality peer-reviewed journal.
(kim2018signalinginthe pages 51-52): Dennis H. Kim and J. Ewbank. Signaling in the innate immune response. WormBook : the online review of C. elegans biology, 2018:1-35, Aug 2018. URL: https://doi.org/10.1895/wormbook.1.83.2, doi:10.1895/wormbook.1.83.2. This article has 152 citations.
(kim2018signalinginthe pages 46-51): Dennis H. Kim and J. Ewbank. Signaling in the innate immune response. WormBook : the online review of C. elegans biology, 2018:1-35, Aug 2018. URL: https://doi.org/10.1895/wormbook.1.83.2, doi:10.1895/wormbook.1.83.2. This article has 152 citations.

Artifacts

Edison artifact artifact-00

Citations

fanelli2023immunitylinkedgenesare pages 1-2
simonsen2012strengthinnumbers pages 5-6
kniazeva2025translationelongationdefects pages 1-2
afridi2025therolesof pages 6-7
anderson2019thefattyacid pages 6-8
xu2023reprogrammingofthe pages 5-6
fanelli2023immunitylinkedgenesare pages 9-12
fanelli2023immunitylinkedgenesare pages 13-14
fanelli2023immunitylinkedgenesare pages 12-13
vasquezrifo2020pseudomonasaeruginosacleaves pages 7-9
kniazeva2025translationelongationdefects pages 3-5
kniazeva2025translationelongationdefects pages 5-6
kniazeva2025translationelongationdefects pages 2-3
fanelli2023immunitylinkedgenesare pages 7-9
fanelli2023immunitylinkedgenesare pages 5-7
kew2020evolutionarilyconservedregulation pages 8-10
kew2020evolutionarilyconservedregulation pages 6-8
kew2020evolutionarilyconservedregulation pages 1-2
kew2020evolutionarilyconservedregulation pages 10-12
xu2023reprogrammingofthe pages 3-5
xu2023reprogrammingofthe pages 7-9
xu2023reprogrammingofthe pages 11-12
xu2023reprogrammingofthe pages 6-7
xu2023reprogrammingofthe pages 9-11
kim2018signalinginthe pages 14-16
balasubramaniam2025unzippingthedefense pages 15-16
kim2018signalinginthe pages 51-52
kim2018signalinginthe pages 46-51
https://doi.org/10.1371/journal.pgen.0020183,
https://doi.org/10.1126/sciadv.adi5545,
https://doi.org/10.4161/viru.21906,
https://doi.org/10.1371/journal.pbio.3000969,
https://doi.org/10.1073/pnas.2423578122,
https://doi.org/10.3390/cells14050327,
https://doi.org/10.1371/journal.ppat.1007893,
https://doi.org/10.7554/elife.57591,
https://doi.org/10.1038/s41467-023-39882-8,
https://doi.org/10.1895/wormbook.1.83.2,
https://doi.org/10.3389/fcimb.2025.1673469,

📚 Additional Documentation

Notes

(irg-2-notes.md)

irg-2 (C49G7.5, WBGene00016783) — research notes

UniProt: O16224 (IRG2_CAEEL). 278 aa. Chromosome V. Gene name irg-2 = "infection
response gene 2". ORF C49G7.5. This is a research journal; provenance is recorded
inline as [PMID:xxxx "verbatim quote"].

Identity / disambiguation

irg-2 = C49G7.5 = WBGene00016783. Confirmed across sources:
UniProt: GN Name=irg-2 {ECO:0000312|WormBase:C49G7.5}; ORFNames=C49G7.5.
Irazoqui et al. 2010 gene table lists [PMID:20617181](https://pubmed.ncbi.nlm.nih.gov/20617181 "C49G7.5, WBGene00016783, AF016418").
Note the paralogous ORFs in the same cosmid (C49G7.7, C49G7.10) are DIFFERENT
genes and must not be conflated with irg-2 (=C49G7.5). Several microarray tables
list C49G7.7 / C49G7.10 separately, so string-matching "C49G7" alone is unsafe.

Protein-level facts (what the sequence tells us)

278 aa, 33 kDa, single CHAIN, no signal peptide, no transmembrane region.
UniProt annotates only a disordered REGION (152–179) with a polar-residue
compositional bias (163–179); no catalytic motif, no recognizable domain.
No PANTHER family assigned at fetch time; UniProt "protein family" field is empty.
Contrast with the paralog-in-name irg-1, which at least carries a predicted
NADAR/YbiA-like domain (IPR012816). irg-2 has NO such domain prediction — it is
even darker at the sequence level than irg-1.
PE=2 (evidence at transcript level): the protein itself has never been detected;
everything known about irg-2 concerns its mRNA induction, not its protein.

KNOWN (established, cited)

1. irg-2 is a transcriptional infection-response gene induced by P. aeruginosa

Estes et al. 2010 defined the "infection response gene" (irg) class as genes
"induced in C. elegans by infection with the bacterial pathogen Pseudomonas
aeruginosa, but ... not induced by an isogenic attenuated gacA mutant"
PMID:20133860.
irg-1 is the named reporter of that class; irg-2 is one of the additional class
members induced by the same virulent-PA14 program. This is the basis of the GOA
IEP annotations (GO:0140367, GO:0050829), both attributed to PMID:20133860.
Troemel et al. 2006 (p38 MAPK microarray study) independently place irg-2 (as
C49G7.5) among the top P. aeruginosa-induced genes at 4 h
PMID:17096597.

2. Induction is via the ZIP-2 bZIP surveillance pathway

Estes et al. 2010: the RNAi TF screen "identified zip-2, a bZIP transcription
factor that is required for inducing irg-1, as well as several other genes"
PMID:20133860.
Hahm et al. 2020 directly measured irg-2 as a ZIP-2 target: it rises with age and
the rise is ZIP-2-dependent
PMID:32350153,
PMID:32350153.
This is the strongest single-gene, full-text-verified statement about irg-2:
irg-2 is a bona fide ZIP-2 transcriptional target, not merely a co-regulated
bystander.

3. Induction is PMK-1 (p38 MAPK) INDEPENDENT

Troemel et al. 2006 tested PMK-1-dependence of the top PA-induced genes and found
irg-2 (C49G7.5) is in the PMK-1-independent set
PMID:17096597.
Consistent with UniProt INDUCTION: dependent on zip-2, independent of pmk-1
p38MAPK, dbl-1 TGF-beta, and kgb-1 JNK pathways (ECO:0000269|PubMed:20133860).

4. Induction is triggered by translational inhibition (surveillance immunity)

Dunbar et al. 2012 showed the zip-2/irg pathway is switched on by pathogen-induced
block of translation, sensed via endocytosed Exotoxin A
PMID:22520465,
and more generally by "disruption of several core host processes, including
inhibition of mRNA translation"
PMID:22520465.
UniProt attributes irg-2 FUNCTION/INDUCTION by ToxA and cycloheximide to this
paper (ECO:0000269|PubMed:22520465). NOTE: the cached PMID_22520465.md is
ABSTRACT-ONLY (full_text_available: false); the abstract names irg-1, not irg-2,
but UniProt curators read the full text and attributed irg-2 to it. Per repo
policy I do not overturn that; I cite the abstract-level surveillance mechanism
and defer irg-2-specific detail to the curator.

5. Broader expression context

HEP annotation (GO:0045087) traces to Shapira et al. 2006, a genome-wide screen
that found endodermal GATA factor ELT-2 governs intestinal infection responses
PMID:16968778.
irg-2 is one of the ELT-2/infection-responsive transcripts in that dataset — hence
the HEP (high-throughput expression pattern) evidence code. This ties irg-2 to the
intestinal epithelium as the likely site of expression.
Bgee (via UniProt) reports expression in pharyngeal muscle cell and 2 other cell
types — consistent with a low-level, tissue-restricted transcript that is
strongly infection-inducible.
irg-2 recurs in later P. aeruginosa / mitochondrial-UPR immunity expression
datasets (Irazoqui et al. 2010, PMID:20617181; the mitochondrial-UPR immunity
study, PMID:25274306) as an infection-responsive transcript, reinforcing that its
signature is transcriptional induction, not a measured activity.

NOT KNOWN (the deliverable for this dark gene)

Molecular function — entirely unknown. No catalytic activity, no binding
partner, no biochemical assay. GOA carries GO:0003674 (molecular_function) as ND.
Unlike irg-1, irg-2 has no domain prediction to even hypothesize an activity.
Is the IRG-2 protein required for defense? Every claim is expression-based
(IEP/HEP). No irg-2 loss-of-function survival phenotype on P. aeruginosa has been
reported; whether IRG-2 protein contributes to resistance vs. is a passive readout
of ZIP-2 activation is undetermined. (Estes 2010 shows zip-2 — the regulator — is
needed for defense; that is not the same as showing irg-2 the effector is.)
Subcellular localization of IRG-2 protein — unknown. It is intestinally
expressed at the tissue level but the protein has never been localized (PE=2).
Direct antimicrobial activity — untested. It is grouped with "antimicrobial
effectors" by pathway position, not by any demonstrated bactericidal/bacteriostatic
activity.
Regulatory logic beyond ZIP-2 — the ZIP-2/CEBP-2 cis-elements in the irg-2
promoter, and whether irg-2 and irg-1 are co-regulated identically, are not mapped.
Conservation / orthology — eggNOG ENOG502TKK2 (Eukaryota) and OrthoDB group
exist, but no functionally characterized ortholog anchors a function; effectively
a nematode-restricted sequence orphan for functional purposes.

Annotation-by-annotation plan (GOA has 4)

GO:0140367 antibacterial innate immune response — IEP, PMID:20133860 → ACCEPT
(BP-level, expression-based; the defining role). Non-core caveat: functional
requirement unproven.
GO:0003674 molecular_function — ND, GO_REF:0000015 → ACCEPT (honestly reflects an
MF-dark gene; this IS the knowledge gap, not a curation defect).
GO:0050829 defense response to Gram-negative bacterium — IEP, PMID:20133860 →
ACCEPT (P. aeruginosa is Gram-negative; specific and expression-supported).
GO:0045087 innate immune response — HEP, PMID:16968778 → ACCEPT (broader parent;
independent high-throughput expression support; C. elegans immunity is all innate).

No REMOVE/MODIFY warranted: all four are expression-based BP/ND annotations that are
internally consistent with the literature. The honest gap is the missing MF, captured
in knowledge_gaps, not fixable by re-labeling an existing annotation.

Deep research provenance note

just deep-research-falcon worm irg-2 --fallback perplexity-lite: the first falcon
attempt timed out (Edison API saturated by many concurrent jobs) and the
perplexity-lite fallback 401'd on quota; the falcon RETRY then succeeded and wrote a
genuine irg-2-deep-research-falcon.md (Edison Scientific Literature, 39 citations,
~1300s). It is committed and cited only for its high-level synthesis that IRG-2 is
functionally uncharacterized ("No enzymatic activity has been assigned to the
protein"), which independently corroborates the GOA ND molecular_function.
IMPORTANT: the falcon report also makes specific claims via unverifiable PMID-token
citations — notably an ENDU-2/heat-stress transcriptional-regulation model (Xu 2023)
and a WormCat/immunity-linked-genes framing (Fanelli 2023), and it alludes to
loss-of-function phenotypes. None of these token citations could be resolved to
cached, PubMed-verified papers, so they are DELIBERATELY NOT imported into the
review. If those papers are later located and verified, the "effector-vs-reporter"
knowledge gap (gap 2) should be revisited. The review otherwise rests on UniProt
(O16224), the GOA TSV, and the six cached publications below, all quote-verified
against the local publications/ cache.

References gathered (verified against cache)

PMID:20133860 Estes 2010 PNAS — irg class definition, zip-2 (abstract-only). HIGH.
PMID:22520465 Dunbar 2012 Cell Host Microbe — translational-inhibition surveillance
(abstract-only; UniProt attributes irg-2 induction). HIGH.
PMID:17096597 Troemel 2006 PLoS Genet — C49G7.5=irg-2 PMK-1-independent (full text). HIGH.
PMID:32350153 Hahm 2020 Aging — irg-2 ZIP-2 target, aging/mito surveillance (full text). HIGH.
PMID:16968778 Shapira 2006 PNAS — ELT-2/intestinal immunity, HEP source (abstract-only). MEDIUM.
(Context only, not added as review refs: PMID:20617181 Irazoqui 2010 gene table;
PMID:25274306 mito-UPR immunity table.)

📄 View Raw YAML

id: O16224
gene_symbol: irg-2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  irg-2 (infection response gene 2; ORF C49G7.5) encodes a 278-residue
  Caenorhabditis elegans protein of unknown molecular function. Its mRNA is a
  transcriptional readout of the intestinal innate immune response: it is strongly
  and specifically induced upon infection with the virulent Gram-negative pathogen
  Pseudomonas aeruginosa (strain PA14) but not by an attenuated (gacA) mutant, and
  its induction requires the bZIP transcription factor ZIP-2 while being independent
  of the PMK-1/p38 MAPK, DBL-1/TGF-beta and KGB-1/JNK immune pathways. Induction is
  triggered by pathogen-imposed blockade of host mRNA translation (surveillance
  immunity) — for example via endocytosed P. aeruginosa Exotoxin A or the chemical
  translation inhibitor cycloheximide — and irg-2 is co-regulated with the
  paralogous marker gene irg-1. Beyond acute infection, irg-2 mRNA accumulates with
  age in a ZIP-2-dependent manner and correlates with mitochondrial damage. The
  IRG-2 protein carries no recognizable catalytic domain or characterized motif
  (only a short disordered, polar-residue region near its C-terminus), has evidence
  only at the transcript level, and has no demonstrated biochemical activity,
  interacting partner, or subcellular localization. Whether the protein itself
  contributes to pathogen resistance, as opposed to serving as a downstream reporter
  of ZIP-2 activation, is not established.
existing_annotations:
  - term:
      id: GO:0140367
      label: antibacterial innate immune response
    evidence_type: IEP
    original_reference_id: PMID:20133860
    qualifier: involved_in
    review:
      summary: >-
        IEP (inferred from expression pattern) annotation: irg-2 is a member of the
        "infection response gene" class defined by Estes et al. 2010 as genes
        specifically induced by virulent P. aeruginosa but not by an attenuated gacA
        mutant. Troemel et al. 2006 independently place irg-2 (as C49G7.5) among the
        top P. aeruginosa-induced genes at 4 h. The evidence is transcriptional
        induction during bacterial infection, which the IEP code accurately reflects.
      action: ACCEPT
      reason: >-
        The annotation correctly captures irg-2's defining, well-replicated property
        — strong and specific transcriptional induction during antibacterial (P.
        aeruginosa) infection — and the IEP evidence code is appropriate for an
        expression-based inference. Retained as a core aspect of the gene. Note the
        boundary of this evidence: it demonstrates induction, not that the IRG-2
        protein is functionally required for the response (see knowledge_gaps).
      supported_by:
        - reference_id: PMID:20133860
          supporting_text: >-
            We focused on genes that are induced in C. elegans by infection with the
            bacterial pathogen Pseudomonas aeruginosa, but are not induced by an
            isogenic attenuated gacA mutant.
        - reference_id: PMID:17096597
          supporting_text: >-
            We tested induction of the top five genes upregulated by P. aeruginosa
            versus E. coli at 4 h
  - term:
      id: GO:0003674
      label: molecular_function
    evidence_type: ND
    original_reference_id: GO_REF:0000015
    qualifier: enables
    review:
      summary: >-
        ND (no data) annotation at the molecular_function root: no molecular function
        has been experimentally determined for IRG-2. The protein has no recognizable
        catalytic domain or characterized motif, and — unlike its co-regulated
        paralog irg-1 (which carries a predicted NADAR/YbiA-like domain) — offers no
        sequence feature from which to even hypothesize an activity.
      action: ACCEPT
      reason: >-
        The ND annotation honestly reflects the current state of knowledge: IRG-2 is
        molecular-function dark. This is a genuine biology knowledge gap (see
        knowledge_gaps), not a curation defect to be repaired by asserting an
        unsupported activity.
      supported_by: []
  - term:
      id: GO:0050829
      label: defense response to Gram-negative bacterium
    evidence_type: IEP
    original_reference_id: PMID:20133860
    qualifier: involved_in
    review:
      summary: >-
        IEP annotation specifying that irg-2's induction occurs in response to a
        Gram-negative bacterium. P. aeruginosa, the pathogen that induces irg-2, is
        Gram-negative, so this is a more specific and appropriate child of the
        antibacterial response term, supported by the same expression evidence.
      action: ACCEPT
      reason: >-
        Accurate and appropriately specific: irg-2 is induced by the Gram-negative
        pathogen P. aeruginosa, and the IEP evidence code matches the expression-based
        source. As with the other IEP term, this reflects induction rather than a
        demonstrated protein-level effector requirement.
      supported_by:
        - reference_id: PMID:20133860
          supporting_text: >-
            This screen identified zip-2, a bZIP transcription factor that is required
            for inducing irg-1, as well as several other genes, and is important for
            defense against infection by P. aeruginosa.
  - term:
      id: GO:0045087
      label: innate immune response
    evidence_type: HEP
    original_reference_id: PMID:16968778
    qualifier: involved_in
    review:
      summary: >-
        HEP (inferred from high-throughput expression pattern) annotation from the
        Shapira et al. 2006 genome-wide study of intestinal infection responses, in
        which the endodermal GATA factor ELT-2 governs a suite of P. aeruginosa-induced
        genes. This is a broader parent of the antibacterial-response terms and
        provides independent high-throughput expression support that irg-2 is part of
        the intestinal innate immune transcriptional program.
      action: ACCEPT
      reason: >-
        Valid and appropriate. C. elegans has only innate immunity, so this general
        term correctly classifies irg-2's immune involvement, and the HEP evidence
        code matches the high-throughput expression source. It is retained as a
        higher-level classification alongside the more specific antibacterial terms.
      supported_by:
        - reference_id: PMID:16968778
          supporting_text: >-
            Gene expression and functional RNAi-based analyses identified the
            tissue-specific GATA transcription factor ELT-2 as a major regulator of an
            early intestinal protective response to infection with the human bacterial
            pathogen Pseudomonas aeruginosa.
references:
  - id: GO_REF:0000015
    title: Use of the ND evidence code for Gene Ontology (GO) terms
    findings:
      - statement: >-
          Standard GO reference for No Data (ND) annotations, used when no
          experimental or computational evidence is available for a given aspect of
          gene function. Applied here to the molecular_function root for irg-2.
  - id: PMID:20133860
    title: >-
      bZIP transcription factor zip-2 mediates an early response to Pseudomonas
      aeruginosa infection in Caenorhabditis elegans.
    findings:
      - statement: >-
          Defines the "infection response gene" (irg) class as genes specifically
          induced by virulent P. aeruginosa but not by an attenuated gacA mutant;
          irg-2 is a member of this class.
        supporting_text: >-
          We focused on genes that are induced in C. elegans by infection with the
          bacterial pathogen Pseudomonas aeruginosa, but are not induced by an
          isogenic attenuated gacA mutant.
      - statement: >-
          The bZIP transcription factor ZIP-2 is required for inducing irg-1 and
          several other infection-response genes and is important for defense against
          P. aeruginosa.
        supporting_text: >-
          This screen identified zip-2, a bZIP transcription factor that is required
          for inducing irg-1, as well as several other genes, and is important for
          defense against infection by P. aeruginosa.
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        PubMed-verified founding paper for the irg class and the ZIP-2 pathway;
        source of the two IEP annotations. Cached record is abstract-only, but the
        irg-2 (=C49G7.5) membership of the induced set is corroborated by full-text
        PMID:17096597 and PMID:32350153.
  - id: PMID:17096597
    title: >-
      p38 MAPK regulates expression of immune response genes and contributes to
      longevity in C. elegans.
    findings:
      - statement: >-
          irg-2 (C49G7.5) is among the top P. aeruginosa-induced genes and is induced
          via a PMK-1 (p38 MAPK)-independent pathway.
        supporting_text: >-
          The remaining two genes (C49G7.5 and F53E10.4) must therefore be induced via
          a PMK-1–independent pathway
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        Full-text-verified. Establishes by ORF name (C49G7.5 = irg-2) that irg-2 is a
        top P. aeruginosa-induced gene whose induction does not require PMK-1,
        independently corroborating the ZIP-2/PMK-1-independent regulatory logic in
        UniProt and PMID:20133860.
  - id: PMID:22520465
    title: >-
      C. elegans detects pathogen-induced translational inhibition to activate immune
      signaling.
    full_text_unavailable: true
    findings:
      - statement: >-
          The zip-2/irg surveillance pathway is activated by pathogen-induced
          inhibition of host mRNA translation, sensed via endocytosed Exotoxin A,
          which raises ZIP-2 protein levels.
        supporting_text: >-
          P. aeruginosa infection inhibits mRNA translation in the intestine via the
          endocytosed translation inhibitor Exotoxin A, which leads to an increase in
          ZIP-2 protein levels.
      - statement: >-
          The zip-2/irg-1 pathway is also induced by disruption of core host
          processes including translational inhibition, independent of infection.
        supporting_text: >-
          In the absence of infection we find that the zip-2/irg-1 pathway is
          upregulated following disruption of several core host processes, including
          inhibition of mRNA translation.
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        PubMed-verified. Establishes the surveillance-immunity trigger (translational
        inhibition) for the zip-2/irg pathway. UniProt attributes irg-2 induction by
        ToxA and cycloheximide to this paper; the cached record is abstract-only (the
        abstract names irg-1), so irg-2-specific detail is deferred to the curator per
        repository policy — not overturned.
  - id: PMID:32350153
    title: A cellular surveillance and defense system that delays aging phenotypes in C. elegans.
    findings:
      - statement: >-
          irg-2 is a bona fide ZIP-2 target whose expression rises strongly with age;
          the age-dependent increase is largely ZIP-2-dependent.
        supporting_text: >-
          the expression of the ZIP-2 targets irg-1 (Figure 2A) and irg-2 (Figure 2B)
          increased 24.0-fold and 15.5-fold, respectively, from day 1 to day 8 of
          adulthood
      - statement: >-
          The age-dependent increases in irg-1 and irg-2 depend on ZIP-2.
        supporting_text: >-
          indicating that the age-dependent increases in irg-1 and irg-2 expression
          were largely dependent on ZIP-2.
    reference_review:
      relevance: HIGH
      correctness: VERIFIED
      review_notes: >-
        Full-text-verified qRT-PCR data explicitly naming irg-2 as a ZIP-2 target.
        Strongest single-gene confirmation that irg-2 is a genuine ZIP-2 pathway
        readout (not just a co-regulated bystander) and extends its context to aging
        and mitochondrial surveillance.
  - id: PMID:16968778
    title: >-
      A conserved role for a GATA transcription factor in regulating epithelial innate
      immune responses.
    findings:
      - statement: >-
          Genome-wide study identifying the endodermal GATA factor ELT-2 as a major
          regulator of the intestinal infection-response transcriptional program that
          includes irg-2.
        supporting_text: >-
          Gene expression and functional RNAi-based analyses identified the
          tissue-specific GATA transcription factor ELT-2 as a major regulator of an
          early intestinal protective response to infection with the human bacterial
          pathogen Pseudomonas aeruginosa.
    reference_review:
      relevance: MEDIUM
      correctness: VERIFIED
      review_notes: >-
        PubMed-verified; source of the HEP annotation. Provides the tissue context
        (intestinal epithelium) and high-throughput expression support, but does not
        address IRG-2 protein function. Cached record is abstract-only.
core_functions:
  - description: >-
      irg-2 acts as a downstream transcriptional effector of the ZIP-2 branch of C.
      elegans surveillance immunity. Its mRNA is a specific, PMK-1-independent readout
      of the intestinal antibacterial defense response, induced when virulent P.
      aeruginosa (or other insults that block host translation) is detected. Its role
      is defined by this regulated expression; the biochemical activity of the IRG-2
      protein and whether it is itself required for pathogen resistance remain
      undetermined.
    directly_involved_in:
      - id: GO:0140367
        label: antibacterial innate immune response
      - id: GO:0050829
        label: defense response to Gram-negative bacterium
    supported_by:
      - reference_id: PMID:20133860
        supporting_text: >-
          We focused on genes that are induced in C. elegans by infection with the
          bacterial pathogen Pseudomonas aeruginosa, but are not induced by an
          isogenic attenuated gacA mutant.
      - reference_id: PMID:32350153
        supporting_text: >-
          the expression of the ZIP-2 targets irg-1 (Figure 2A) and irg-2 (Figure 2B)
          increased 24.0-fold and 15.5-fold, respectively, from day 1 to day 8 of
          adulthood
knowledge_gaps:
  - gap_statement: >-
      The molecular function of IRG-2 is undetermined. No catalytic, binding, or
      antimicrobial activity has been demonstrated, no physical interaction partner is
      known, and — unlike its co-regulated paralog irg-1, which carries a predicted
      NADAR/YbiA-like domain — the protein has no recognizable domain from which to
      even hypothesize an activity.
    boundary: >-
      irg-2 is a well-established transcriptional readout of the ZIP-2
      surveillance-immunity pathway: strongly and specifically induced by virulent P.
      aeruginosa (PMID:20133860), by translational inhibition (Exotoxin A /
      cycloheximide; PMID:22520465), and with age in a ZIP-2-dependent manner
      (PMID:32350153), independent of PMK-1 p38 MAPK (PMID:17096597). The 278-aa
      protein has only a short disordered/polar-residue region and no catalytic motif,
      and evidence exists solely at the transcript level (UniProt PE=2).
    gap_kind:
      - BIOLOGY
    dark_aspect: MF_DARK
    status: OPEN
    significance: >-
      irg-2 is one of the canonical downstream effectors invoked to define the ZIP-2
      arm of C. elegans surveillance immunity, yet what its protein product actually
      does — enzyme, antimicrobial effector, or inert reporter — is entirely unknown,
      leaving the effector output of this well-studied pathway mechanistically blank.
    resolution: >-
      Recombinant-protein biochemistry and/or structure determination to test for an
      enzymatic or antimicrobial activity; affinity/proximity proteomics (AP-MS) or
      yeast two-hybrid to identify partners; endogenous tagging for subcellular
      localization.
    provenance:
      - reference_id: file:worm/irg-2/irg-2-goa.tsv
        supporting_text: "GO:0003674\tmolecular_function\tmolecular_function\tECO:0000307\tND"
      - reference_id: file:worm/irg-2/irg-2-deep-research-falcon.md
        supporting_text: >-
          No enzymatic activity has been assigned to the protein.
      - reference_id: PMID:32350153
        supporting_text: >-
          the expression of the ZIP-2 targets irg-1 (Figure 2A) and irg-2 (Figure 2B)
  - gap_statement: >-
      It is unknown whether the IRG-2 protein is functionally required for defense
      against P. aeruginosa. All evidence linking irg-2 to immunity is transcriptional
      (IEP/HEP); no irg-2 loss-of-function survival, colonization, or immune phenotype
      has been reported, so whether IRG-2 is a causal effector or a passive reporter of
      ZIP-2 activation is unresolved.
    boundary: >-
      The regulator ZIP-2 is required for defense against P. aeruginosa
      (PMID:20133860), and irg-2 is a ZIP-2-dependent target (PMID:32350153); but
      requirement of the regulator does not establish requirement of this particular
      target. irg-2's association with defense rests entirely on expression
      correlation, not on perturbation of irg-2 itself.
    gap_kind:
      - BIOLOGY
    status: OPEN
    significance: >-
      Distinguishing effector from reporter is essential before irg-2 can be assigned a
      causal role in innate immunity, and would clarify whether the ZIP-2 pathway's
      protective output runs through irg-2 or through other, as-yet-unidentified
      effectors.
    resolution: >-
      Loss-of-function (deletion/RNAi) and overexpression of irg-2 with quantitative
      survival and bacterial-burden assays on P. aeruginosa PA14, ideally with rescue,
      to test whether IRG-2 protein is required for or sufficient to enhance resistance.
    provenance:
      - reference_id: PMID:20133860
        supporting_text: >-
          is important for defense against infection by P. aeruginosa.
proposed_new_terms: []
suggested_questions:
  - question: >-
      Does the IRG-2 protein have any enzymatic or direct antimicrobial activity, or
      is it an inert transcriptional reporter of ZIP-2 activation?
  - question: >-
      Is irg-2 loss-of-function associated with any measurable susceptibility to P.
      aeruginosa (survival or bacterial burden)?
  - question: >-
      Where does IRG-2 protein localize within intestinal (and pharyngeal) cells, and
      is it secreted?
  - question: >-
      Do irg-1 and irg-2 act redundantly or on distinct targets within the ZIP-2
      surveillance program?
suggested_experiments:
  - description: >-
      Generate an irg-2 deletion (and irg-1;irg-2 double) and assay survival and
      intestinal bacterial burden on P. aeruginosa PA14 versus control bacteria, with
      transgenic rescue, to test whether IRG-2 protein is required for defense.
    hypothesis: >-
      IRG-2 is a functional effector required for wild-type resistance to P.
      aeruginosa, not merely a downstream reporter.
  - description: >-
      Express and purify recombinant IRG-2 and screen for candidate biochemical
      activities and for direct antibacterial activity against P. aeruginosa in vitro;
      determine its structure (experimental or from AlphaFold) to search for cryptic
      active-site or fold features.
    hypothesis: >-
      IRG-2 possesses a discrete molecular activity (enzymatic or antimicrobial) that
      its lack of an annotated domain has obscured.
  - description: >-
      Use endogenous fluorescent tagging plus affinity/proximity proteomics (AP-MS) of
      IRG-2 in infected animals to determine subcellular localization and physical
      interaction partners.
    hypothesis: >-
      IRG-2 localizes to a defined compartment (e.g. secretory/apical intestinal) and
      acts through specific protein partners.
tags: [caeel-surveillance-immunity]

irg-2

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

Tags

Deep Research

Falcon

Comprehensive Research Report: irg-2 (Infection Response Gene 2, C49G7.5) in Caenorhabditis elegans

1. Gene Identity and Overview

2. Transcriptional Regulation and Signaling Pathway Context

2.1 PMK-1-Independent Induction (Class D Pathogen Response Gene)

2.2 ZIP-2 bZIP Transcription Factor Pathway

2.3 TGF-β/DBL-1 Signaling Pathway

2.4 ARF-1 GTPase and Golgi Membrane Stress Pathway

2.5 Oleate Requirement

2.6 Negative Regulation by RNP-6/PUF60

2.7 ENDU-2-Mediated Post-Heat Stress Regulation

3. Tissue Expression and Subcellular Localization

4. Molecular Function and Protein Characteristics

5. Induction Specificity

6. Broader Biological Roles

6.1 Heat Hormesis and Stress Resistance

6.2 Integration with Metabolic Regulation

7. Summary

Artifacts

Citations

📚 Additional Documentation

Notes

irg-2 (C49G7.5, WBGene00016783) — research notes

Identity / disambiguation

Protein-level facts (what the sequence tells us)

KNOWN (established, cited)

1. irg-2 is a transcriptional infection-response gene induced by P. aeruginosa

2. Induction is via the ZIP-2 bZIP surveillance pathway

3. Induction is PMK-1 (p38 MAPK) INDEPENDENT

4. Induction is triggered by translational inhibition (surveillance immunity)

5. Broader expression context

NOT KNOWN (the deliverable for this dark gene)

Annotation-by-annotation plan (GOA has 4)

Deep research provenance note

References gathered (verified against cache)

📄 View Raw YAML