Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: PEK-1 is a well-established eIF2alpha kinase. The IBA annotation is consistent with phylogenetic conservation and experimental evidence from C. elegans studies showing that PEK-1 phosphorylates eIF2alpha to attenuate translation during ER stress (PMID:10677345, PMID:11779465, PMID:22125500). Reason: This is the core molecular function of PEK-1. Direct evidence from expression of C. elegans PEK in yeast demonstrated eIF2alpha hyperphosphorylation (PMID:10677345). The IBA annotation correctly captures the conserved kinase activity at the appropriate level of specificity. Supporting Evidence: PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C. file:worm/pek-1/pek-1-deep-research-falcon.md model: Edison Scientific Literature
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Nuclear localization is suggested by phylogenetic inference from mammalian PERK, which can translocate to the nucleus under certain conditions. However, the primary localization of PEK-1 is at the ER membrane as a type I transmembrane protein. Reason: While PERK family members may have nuclear functions, the core localization and function of PEK-1 is at the ER membrane. This annotation may reflect a secondary or conditional localization rather than the primary site of function. UniProt annotation indicates ER membrane as the primary location. Supporting Evidence: UniProt:Q19192
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: The cytoplasmic domain of PEK-1 contains the kinase domain that phosphorylates eIF2alpha in the cytoplasm. This annotation reflects that the kinase domain faces the cytoplasm. Reason: PEK-1 is a type I transmembrane protein with a large cytoplasmic kinase domain (aa 475-1077 per UniProt). The kinase activity occurs in the cytoplasm where eIF2alpha substrates reside. This is consistent with the protein topology. Supporting Evidence: UniProt:Q19192
GO:0006446 regulation of translational initiation	IBA GO_REF:0000033	ACCEPT	Summary: PEK-1 regulates translation initiation by phosphorylating eIF2alpha, which is a key step in translational initiation control. This is a core biological process for PEK-1. Reason: The phosphorylation of eIF2alpha by PEK-1 directly regulates translational initiation. This is consistent with experimental evidence and the conserved function of PERK kinases. Supporting Evidence: PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C.
GO:0017148 negative regulation of translation	IBA GO_REF:0000033	ACCEPT	Summary: PEK-1 negatively regulates global translation through eIF2alpha phosphorylation, leading to reduced translation initiation and global protein synthesis attenuation during ER stress. Reason: This is a direct consequence of PEK-1's eIF2alpha kinase activity. Phosphorylation of eIF2alpha leads to global translational repression, which is the primary outcome of PEK-1 activation during stress. Supporting Evidence: UniProt:Q19192
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: PEK-1 contains an ATP-binding domain typical of protein kinases. This is inferred from UniProt keyword mapping and is consistent with the kinase activity. Reason: As a protein kinase, PEK-1 requires ATP binding for its catalytic activity. This is a true but generic annotation that follows from the kinase function. The annotation is correct but less informative than the more specific ATP binding annotation. Supporting Evidence: UniProt:Q19192
GO:0004672 protein kinase activity	IEA GO_REF:0000002	ACCEPT	Summary: PEK-1 is a protein kinase that phosphorylates eIF2alpha. This annotation is correct but less specific than the eIF2alpha kinase activity annotation. Reason: This is a correct parent term annotation. While less specific than GO:0004694 (eIF2alpha kinase activity), it accurately reflects PEK-1's function. The IEA annotation from InterPro correctly identifies the protein kinase domain. Supporting Evidence: UniProt:Q19192
GO:0004674 protein serine/threonine kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: PEK-1 is a serine/threonine kinase that phosphorylates eIF2alpha at a serine residue. This is confirmed by the catalytic activity annotations in UniProt. Reason: This annotation correctly specifies PEK-1 as a Ser/Thr kinase. The catalytic activity is well-documented for phosphorylation of serine and threonine residues on protein substrates. Supporting Evidence: UniProt:Q19192
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: PEK-1 contains an ATP binding site typical of protein kinases, required for its kinase activity. Reason: ATP binding is essential for PEK-1 kinase activity. The protein contains conserved ATP binding motifs in the kinase domain. Supporting Evidence: UniProt:Q19192
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: PEK-1 is a type I transmembrane protein localized to the ER membrane, where it senses ER stress through its lumenal domain and transmits signals to the cytoplasm. Reason: ER membrane localization is the primary and essential localization for PEK-1 function. The lumenal domain senses unfolded proteins, triggering oligomerization and activation of the cytoplasmic kinase domain. Supporting Evidence: UniProt:Q19192 PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress.
GO:0006417 regulation of translation	IEA GO_REF:0000043	ACCEPT	Summary: PEK-1 regulates translation through phosphorylation of eIF2alpha. This is a broader parent term for its role in translation regulation. Reason: This is a correct but generic annotation. More specific child terms (regulation of translational initiation, negative regulation of translation) are also annotated and provide better specificity. Supporting Evidence: PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C.
GO:0006986 response to unfolded protein	IEA GO_REF:0000043	ACCEPT	Summary: PEK-1 is activated by accumulation of unfolded proteins in the ER lumen and is a core component of the Unfolded Protein Response. Reason: This is a fundamental aspect of PEK-1 function. The protein is activated by ER stress caused by unfolded proteins and mediates a key arm of the UPR. Supporting Evidence: PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. UniProt:Q19192
GO:0016301 kinase activity	IEA GO_REF:0000043	ACCEPT	Summary: PEK-1 has kinase activity, specifically as a serine/threonine protein kinase. Reason: This is a correct but very generic parent term. The annotation is accurate but provides less information than the more specific kinase activity terms also annotated. Supporting Evidence: UniProt:Q19192
GO:0016740 transferase activity	IEA GO_REF:0000043	ACCEPT	Summary: As a kinase, PEK-1 transfers phosphate groups and thus has transferase activity. Reason: This is a correct but extremely generic parent term annotation. All kinases have transferase activity. While accurate, more specific terms provide better functional characterization. Supporting Evidence: UniProt:Q19192
GO:0034976 response to endoplasmic reticulum stress	IEA GO_REF:0000117	ACCEPT	Summary: PEK-1 is activated by ER stress and mediates the translational attenuation arm of the ER stress response. Reason: This is a core biological process for PEK-1. The protein is one of the three main sensors of ER stress in metazoans and mediates protective responses to ER stress. Supporting Evidence: PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C. PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress.
GO:0106310 protein serine kinase activity	IEA GO_REF:0000116	ACCEPT	Summary: PEK-1 phosphorylates serine residues on protein substrates including eIF2alpha. Reason: This annotation correctly identifies PEK-1's serine kinase activity based on the Rhea reaction annotation in UniProt. EIF2alpha is phosphorylated at a serine residue. Supporting Evidence: UniProt:Q19192
GO:1904688 regulation of cytoplasmic translational initiation	IGI PMID:22719267 Protective coupling of mitochondrial function and protein sy...	ACCEPT	Summary: This annotation from PMID:22719267 examines GCN-2 rather than PEK-1 as the primary subject. The paper studies the role of GCN-2 in mitochondrial stress and includes gcn-2;pek-1 double mutants to examine eIF2alpha phosphorylation. Reason: The paper demonstrates that PEK-1 and GCN-2 have overlapping roles in eIF2alpha phosphorylation and translational regulation. The IGI annotation is appropriate as it shows genetic interaction between pek-1 and gcn-2 in regulating cytoplasmic translation initiation. Supporting Evidence: PMID:22719267 Jun 14. Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.
GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity	IGI PMID:22125500 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabdi...	ACCEPT	Summary: PMID:22125500 (Richardson et al. 2011) demonstrates that XBP-1 deficiency increases PEK-1 dependent phosphorylation of eIF2alpha, providing genetic interaction evidence for PEK-1's eIF2alpha kinase activity. Reason: This IGI annotation is supported by experimental evidence showing PEK-1-dependent eIF2alpha phosphorylation in xbp-1 mutant backgrounds. The genetic interaction with xbp-1 demonstrates PEK-1's kinase activity in vivo. Supporting Evidence: PMID:22125500 2011 Nov 17. Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity.
GO:0030968 endoplasmic reticulum unfolded protein response	IMP PMID:22125500 Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabdi...	ACCEPT	Summary: PMID:22125500 demonstrates that PEK-1 functions in the ER unfolded protein response alongside IRE-1/XBP-1, with both pathways maintaining ER homeostasis under physiological conditions. Reason: This is a core biological process for PEK-1. The IMP evidence is strong, showing that pek-1 mutants have altered ER stress responses and that xbp-1;pek-1 double mutants show synthetic phenotypes indicative of essential UPR function. Supporting Evidence: PMID:22125500 2011 Nov 17. Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity.
GO:0036499 PERK-mediated unfolded protein response	IMP PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	ACCEPT	Summary: PMID:11779465 (Shen et al. 2001) established that pek-1 mediates a distinct arm of the UPR through translational attenuation, acting in complementary pathways with IRE-1/XBP-1. Reason: This is the most specific and accurate term for PEK-1's role in the UPR. The IMP evidence from this foundational paper demonstrates PEK-1's function in mediating translational attenuation during ER stress. Supporting Evidence: PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C.
GO:0036499 PERK-mediated unfolded protein response	IGI PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	ACCEPT	Summary: PMID:11779465 shows genetic interactions between pek-1 and ire-1/xbp-1, demonstrating that PEK-1 acts in a complementary pathway for the UPR. Reason: The IGI evidence demonstrates that pek-1 and ire-1/xbp-1 function in complementary pathways, with double mutants showing synthetic developmental defects. This genetic interaction supports PEK-1's role in the PERK-mediated UPR. Supporting Evidence: PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C.
GO:0030968 endoplasmic reticulum unfolded protein response	IMP PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	ACCEPT	Summary: PMID:11779465 demonstrates through mutant phenotype analysis that PEK-1 functions in the ER UPR. Reason: This IMP annotation is well-supported by the mutant phenotype data showing that pek-1 mutants are sensitized to ER stress and that combined loss of pek-1 with other UPR branches causes developmental arrest. Supporting Evidence: PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C. UniProt:Q19192
GO:0030968 endoplasmic reticulum unfolded protein response	IGI PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	ACCEPT	Summary: PMID:11779465 demonstrates genetic interactions between pek-1 and other UPR components (ire-1, xbp-1) showing that PEK-1 functions in the ER UPR. Reason: The IGI evidence from genetic interaction studies with ire-1/xbp-1 strongly supports PEK-1's role in the ER UPR. Double mutants show synthetic developmental arrest. Supporting Evidence: PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C.
GO:0002119 nematode larval development	IGI PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	KEEP AS NON CORE	Summary: PMID:11779465 shows that pek-1 functions in larval development, with xbp-1;pek-1 or ire-1;pek-1 double mutants arresting at larval stages. Reason: While pek-1 is required for normal larval development (especially in combination with other UPR mutants), developmental regulation is not the core molecular function of PEK-1. This represents a pleiotropic consequence of its role in ER homeostasis rather than a primary function. Supporting Evidence: PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C. UniProt:Q19192
GO:0004694 eukaryotic translation initiation factor 2alpha kinase activity	IDA PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ...	ACCEPT	Summary: PMID:10677345 (Sood et al. 2000) provides direct experimental evidence that C. elegans PEK phosphorylates eIF2alpha when expressed in yeast, inhibiting growth through hyperphosphorylation of eIF2alpha and inhibition of eIF2B. Reason: This is the strongest experimental evidence for PEK-1's eIF2alpha kinase activity. The IDA annotation is based on direct assay of the kinase activity in a heterologous yeast system. Supporting Evidence: PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress.
GO:0005789 endoplasmic reticulum membrane	ISS PMID:11779465 Complementary signaling pathways regulate the unfolded prote...	ACCEPT	Summary: PMID:11779465 supports ER membrane localization based on sequence similarity to mammalian PERK, which is established as an ER membrane protein. Reason: The ISS annotation is appropriate given the strong sequence conservation with mammalian PERK and the conserved domain architecture including a signal peptide, lumenal domain, transmembrane domain, and cytoplasmic kinase domain. Supporting Evidence: UniProt:Q19192 PMID:11779465 Complementary signaling pathways regulate the unfolded protein response and are required for C.
GO:0045947 negative regulation of translational initiation	IC PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) ...	ACCEPT	Summary: PMID:10677345 provides the basis for inferring that PEK-1 negatively regulates translational initiation through eIF2alpha phosphorylation, which inhibits eIF2B and prevents translation initiation. Reason: The IC annotation appropriately captures the logical inference from the demonstrated eIF2alpha kinase activity to its regulatory consequence on translational initiation. Phosphorylated eIF2alpha inhibits eIF2B, preventing GDP-GTP exchange needed for translation initiation. Supporting Evidence: PMID:10677345 Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress. UniProt:Q19192
GO:0035966 response to topologically incorrect protein	IMP PMID:23335331 A novel interaction between aging and ER overload in a prote...	ACCEPT	Summary: PMID:23335331 (Schipanski et al. 2013) uses a C. elegans model of FENIB (familial encephalopathy with neuroserpin inclusion bodies) to show that UPR pathways including PEK-1 modulate protein aggregation and respond to misfolded proteins. Reason: The annotation captures PEK-1's role in responding to topologically incorrect/misfolded proteins. The paper shows that downregulation of UPR pathways (including pek-1) favors mutant protein accumulation. Supporting Evidence: PMID:23335331 Jan 18. A novel interaction between aging and ER overload in a protein conformational dementia.
GO:0035966 response to topologically incorrect protein	IGI PMID:23335331 A novel interaction between aging and ER overload in a prote...	ACCEPT	Summary: PMID:23335331 demonstrates genetic interactions showing that PEK-1 and other UPR components respond to topologically incorrect proteins (aggregating neuroserpin mutants). Reason: The IGI annotation reflects genetic interaction evidence where loss of pek-1 in combination with other UPR mutations affects the response to misfolded proteins. Supporting Evidence: PMID:23335331 Jan 18. A novel interaction between aging and ER overload in a protein conformational dementia.

Core Functions

Direct experimental evidence from PMID:10677345 showing C. elegans PEK phosphorylates eIF2alpha in yeast expression system; supported by genetic studies in PMID:11779465 and PMID:22125500 demonstrating PEK-1-dependent eIF2alpha phosphorylation.

Molecular Function:

eukaryotic translation initiation factor 2alpha kinase activity

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

GO_REF:0000116

Automatic Gene Ontology annotation based on Rhea mapping

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10677345

Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) homologues in humans, Drosophila melanogaster and Caenorhabditis elegans that mediate translational control in response to endoplasmic reticulum stress.

Identified and characterized C. elegans PEK; demonstrated eIF2alpha kinase activity in yeast expression system; showed PEK inhibits translation through eIF2alpha hyperphosphorylation and eIF2B inhibition.

"To address the role of C. elegans PEK in translational control, we expressed this kinase in yeast and found that it inhibits growth by hyperphosphorylation of eIF-2alpha and inhibition of eIF-2B."

PMID:11779465

Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development.

Established that pek-1 mediates translation attenuation arm of UPR; showed pek-1 acts in complementary pathways with ire-1/xbp-1 for development and survival; demonstrated synthetic lethality of double UPR mutants.

"In addition, ire-1/xbp-1 acts with pek-1, a protein kinase that mediates translation attenuation, in complementary pathways that are essential for worm development and survival."

PMID:22125500

Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis elegans larval development and immunity.

Demonstrated increased PEK-1-dependent eIF2alpha phosphorylation in xbp-1 mutants; defined temperature-dependent requirements for XBP-1 and PEK-1; showed both pathways maintain ER homeostasis under physiological conditions including immune activation.

"XBP-1 deficiency increases PEK-1 dependent phosphorylation of eIF2α."

PMID:22719267

Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2.

Demonstrated GCN-2 and PEK-1 have overlapping roles in eIF2alpha phosphorylation; showed gcn-2;pek-1 double mutants in context of mitochondrial stress studies.

"GCN-2, an eIF2α kinase that modulates cytosolic protein synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1."

PMID:23335331

A novel interaction between aging and ER overload in a protein conformational dementia.

Used C. elegans FENIB model to show UPR pathways including PEK-1 modulate aggregation of misfolded proteins; downregulation of UPR pathways favors mutant protein accumulation.

"Specifically, downregulation of the unfolded protein response (UPR) pathways in the worm favors mutant SRP-2 accumulation"

file:worm/pek-1/pek-1-deep-research-falcon.md

Deep research report on pek-1

Suggested Experiments

Experiment: Phosphoproteomics in pek-1 mutants vs wild-type under ER stress to identify additional PEK-1 substrates beyond eIF2alpha. Recent evidence suggests eIF2alpha-independent functions of PEK-1; identifying additional substrates would provide mechanistic insight.

Experiment: Tissue-specific rescue experiments to determine which tissues require PEK-1 for different stress responses (ER stress, replication stress, immune activation). PEK-1 has been shown to function in intestine and ASI neurons; systematic tissue-specific analysis would define where PEK-1 is required for each stress response.

📚 Additional Documentation

Deep Research Falcon

(pek-1-deep-research-falcon.md)

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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: Q19192
Protein Description: RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase pek-1 {ECO:0000305|PubMed:10677345}; EC=2.7.11.1 {ECO:0000269|PubMed:10677345}; AltName: Full=CePEK; Short=PEK; AltName: Full=PRKR-like endoplasmic reticulum kinase; Short=PERK; Flags: Precursor;
Gene Information: Name=pek-1; ORFNames=F46C3.1;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. Ser/Thr protein
Key Domains: CC_SR_Kinase. (IPR050339); Kinase-like_dom_sf. (IPR011009); PQQ_b-propeller_rpt. (IPR018391); Prot_kinase_dom. (IPR000719); Protein_kinase_ATP_BS. (IPR017441)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "pek-1" 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 'pek-1' 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 pek-1 (gene ID: pek-1, UniProt: Q19192) 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: Q19192
Protein Description: RecName: Full=Eukaryotic translation initiation factor 2-alpha kinase pek-1 {ECO:0000305|PubMed:10677345}; EC=2.7.11.1 {ECO:0000269|PubMed:10677345}; AltName: Full=CePEK; Short=PEK; AltName: Full=PRKR-like endoplasmic reticulum kinase; Short=PERK; Flags: Precursor;
Gene Information: Name=pek-1; ORFNames=F46C3.1;
Organism (full): Caenorhabditis elegans.
Protein Family: Belongs to the protein kinase superfamily. Ser/Thr protein
Key Domains: CC_SR_Kinase. (IPR050339); Kinase-like_dom_sf. (IPR011009); PQQ_b-propeller_rpt. (IPR018391); Prot_kinase_dom. (IPR000719); Protein_kinase_ATP_BS. (IPR017441)

MANDATORY VERIFICATION STEPS:

Check if the gene symbol "pek-1" 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 pek-1 (gene ID: pek-1, UniProt: Q19192) 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.

Plan overview: We verified the target as Caenorhabditis elegans pek-1 (PERK ortholog; UniProt Q19192) and gathered primary literature on its function, genetic interactions, and recent findings (2023–2024). We synthesized molecular function, pathways, phenotypes, localization, and quantitative outcomes where available.

Executive summary
- Identity and context: pek-1 encodes the Caenorhabditis elegans ortholog of PERK, a type I ER transmembrane Ser/Thr kinase that phosphorylates eIF2α to initiate the integrated stress response (ISR) during the ER unfolded protein response (UPR-ER). It functions alongside ire-1/xbp-1 and atf-6 branches to maintain ER homeostasis, with partly overlapping and context-specific roles (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 110-118).
- Recent advances (2023–2024): Replication fork stalling activates the UPR-ER including the PEK-1 branch, and loss of pek-1 sensitizes animals to hydroxyurea-induced replication stress, impairing growth and developmental progression (Xu et al., G3, Jan 2024; DOI: 10.1093/g3journal/jkae017; URL: https://doi.org/10.1093/g3journal/jkae017) (xu2024theunfoldedprotein pages 11-12, xu2024theunfoldedprotein pages 9-9, xu2024theunfoldedprotein pages 4-5). Under ER stress, PERK/PEK-1-mediated eIF2α phosphorylation is required for translational attenuation and survival, whereas dietary-restriction–associated translational changes and lifespan extension can occur without eIF2α phosphorylation; combined loss of gcn-2 and pek-1 abolishes DR-induced lifespan extension (Ma et al., Frontiers in Cell and Developmental Biology, Dec 14, 2023; DOI: 10.3389/fcell.2023.1263344; URL: https://doi.org/10.3389/fcell.2023.1263344) (ma2023theintegratedstress pages 1-2).

1) Key concepts and definitions
- Molecular function: PEK-1 is the eIF2α kinase of the UPR-ER/ISR in C. elegans. Upon ER stress, PEK-1 phosphorylates eIF2α to decrease general translation and reprogram selective mRNA translation, thereby reducing ER protein-folding load (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 110-118). In neuronal contexts, PEK-1 phosphorylates eIF2α on Ser49 (worm site) to control developmental outcomes (see dauer section) (kulalert2017geneticanalysisof pages 22-26). Mechanistically, this maps to the conserved PERK role in ISR (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 110-118).
- Activation context: ER stressors (misfolded proteins), heightened secretory/immune activity, and elevated physiological temperature activate UPR-ER sensors including PEK-1 (richardson2011physiologicalire1xbp1anda pages 138-146, richardson2011physiologicalire1xbp1anda pages 110-118). XBP-1 deficiency causes constitutive ER stress with elevated basal PEK-1 activity (richardson2011physiologicalire1xbp1anda pages 138-146, richardson2011physiologicalire1xbp1anda pages 110-118).
- Pathway placement: PEK-1 is one of three canonical ER stress sensors (with IRE-1/XBP-1 and ATF-6) that coordinate ER proteostasis via translational attenuation, ER chaperone/ERAD induction, and ER expansion (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 110-118). PEK-1 regulates a distinct subset of inducible UPR genes and acts partly redundantly with other branches during development (richardson2011physiologicalire1xbp1anda pages 110-118).

2) Recent developments and latest research (prioritizing 2023–2024)
- Replication stress → UPR-ER engagement: Replication fork stalling induced by primase depletion (pri-1/pri-2 RNAi), UV–C, or hydroxyurea (HU) selectively activates the UPR-ER in C. elegans embryos and soma. The PEK-1 branch is activated by primase depletion and is required together with IRE-1 for somatic resistance to prolonged HU exposure; atf-6 was not required in these HU paradigms (Xu et al., G3, Jan 2024; URL: https://doi.org/10.1093/g3journal/jkae017; Advance Access Jan 24, 2024) (xu2024theunfoldedprotein pages 8-9, xu2024theunfoldedprotein pages 1-1, xu2024theunfoldedprotein pages 11-12, xu2024theunfoldedprotein pages 9-9, xu2024theunfoldedprotein pages 4-5, xu2024theunfoldedprotein pages 10-11).
- Reported outcomes: Under HU (15 mM from L1), pek-1 mutants exhibit reduced average body size and reduced progression past L4 within 48 h relative to wild type; ire-1 mutants are similarly sensitized, whereas atf-6 mutants are not (xu2024theunfoldedprotein pages 8-9, xu2024theunfoldedprotein pages 9-9).
- ISR in physiology and aging: Under ER stress, PEK-1 and eIF2α phosphorylation are required for translational repression and survival. Under dietary restriction (DR), changes in translation, nonsense-mediated decay, and lifespan extension did not require eIF2α phosphorylation; however, loss of both gcn-2 and pek-1 abolished DR-induced lifespan extension, suggesting PEK-1 and GCN2 have eIF2α-independent roles or overlapping substrates (Ma et al., Frontiers in Cell and Developmental Biology, Dec 14, 2023; URL: https://doi.org/10.3389/fcell.2023.1263344) (ma2023theintegratedstress pages 1-2).

3) Current applications and real-world implementations
- ER stress and immunity/temperature: Physiological UPR-ER is engaged by innate immune activation and elevated temperature; PEK-1 functions in parallel with IRE-1/XBP-1 to maintain ER homeostasis and organismal viability under these physiological challenges (PLoS Genetics, 2011; URL: https://doi.org/10.1371/journal.pgen.1002391) (richardson2011physiologicalire1xbp1anda pages 138-146).
- Genetic interaction mapping and UPR transcriptomics: Combining UPR-ER branch mutations (e.g., ire-1/xbp-1 with pek-1 or atf-6) causes larval arrest, illustrating essential redundancy. PEK-1 is required for induction of a portion of inducible UPR genes (~23%), aiding functional dissection of ER stress networks and enabling system-level modeling of ER proteostasis in vivo (PLoS Genetics, 2005; URL: https://doi.org/10.1371/journal.pgen.0010037) (richardson2011physiologicalire1xbp1anda pages 110-118).
- Developmental plasticity circuits: Neuron-specific PEK-1 (ASI neurons) controls dauer entry via eIF2α phosphorylation, a paradigm used to dissect cell-type–specific ISR control over organismal developmental decisions (kulalert2017geneticanalysisof pages 22-26, kulalert2017geneticanalysisof pages 17-22).

4) Expert opinions and analysis from authoritative sources
- Foundational genetic analyses emphasize complementary roles of UPR-ER branches: in C. elegans, single-branch mutants are viable but double-branch disruptions arrest, indicating that PEK-1 complements IRE-1/XBP-1 and ATF-6 to sustain development and homeostasis (Shen et al., PLoS Genetics 2005; URL: https://doi.org/10.1371/journal.pgen.0010037) (richardson2011physiologicalire1xbp1anda pages 110-118). Physiological analyses argue that PEK-1 is required to buffer increased ER load during immune activation and at higher temperatures, with dynamic requirements for each branch depending on context (Richardson et al., PLoS Genetics 2011; URL: https://doi.org/10.1371/journal.pgen.1002391) (richardson2011physiologicalire1xbp1anda pages 138-146, richardson2011physiologicalire1xbp1anda pages 110-118).
- 2024 perspective: Xu et al. extend UPR-ER relevance beyond proteostasis to genome maintenance, arguing that UPR-ER activation (including PEK-1) confers protection against DNA damage arising from replication fork stalling. Their transcriptomics link replication stress to ER processes (protein glycosylation, calcium signaling, fatty acid desaturation), supporting crosstalk between replication dynamics and ER homeostasis (G3, 2024; URL: https://doi.org/10.1093/g3journal/jkae017) (xu2024theunfoldedprotein pages 11-12, xu2024theunfoldedprotein pages 10-11).
- 2023 ISR physiology: Ma et al. argue that eIF2α phosphorylation is dispensable for DR-driven translational and lifespan responses, yet PERK/PEK-1 remains essential under ER stress, highlighting context-specific ISR dependencies and likely additional PERK substrates (Frontiers in Cell and Developmental Biology, 2023; URL: https://doi.org/10.3389/fcell.2023.1263344) (ma2023theintegratedstress pages 1-2).

5) Relevant statistics and data from recent studies
- Replication stress outcomes (HU paradigm): With 15 mM HU exposure initiated at L1, pek-1 mutants show decreased body size and reduced fraction progressing past L4 at 48 h relative to wild type, indicating sensitization; ire-1 mutants exhibit similar sensitivity, while atf-6 is dispensable in this assay (Xu et al., 2024; URL: https://doi.org/10.1093/g3journal/jkae017). The study also used pri-1/pri-2 RNAi and UV–C to induce replication stress and monitored hsp-4p::GFP induction, establishing selective UPR-ER activation (xu2024theunfoldedprotein pages 8-9, xu2024theunfoldedprotein pages 9-9, xu2024theunfoldedprotein pages 11-12).
- UPR-ER transcriptional control: PEK-1 contributes to induction of approximately 23% of inducible UPR genes, defining its specific transcriptional footprint within the inducible ER stress program (Shen et al., PLoS Genetics, 2005; URL: https://doi.org/10.1371/journal.pgen.0010037) (richardson2011physiologicalire1xbp1anda pages 110-118).
- Dietary restriction physiology: DR-linked lifespan extension is lost with concomitant loss of gcn-2 and pek-1, while translational changes under DR do not require eIF2α phosphorylation, indicating that ISR components contribute via eIF2α-dependent and independent mechanisms depending on context (Ma et al., 2023; URL: https://doi.org/10.3389/fcell.2023.1263344) (ma2023theintegratedstress pages 1-2).

Functional annotation for pek-1 (C. elegans; UniProt Q19192)
- Enzymatic activity: Ser/Thr protein kinase that phosphorylates the eIF2α subunit to attenuate translation initiation during ER stress, initiating the ISR arm of the UPR-ER (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 110-118). In neurons, PEK-1-dependent phosphorylation occurs at eIF2α Ser49 (functional genetic evidence) (kulalert2017geneticanalysisof pages 22-26).
- Activation and upstream signals: Activated by accumulation of misfolded proteins in the ER, by physiological immune signaling that increases secretory demand, and by elevated temperatures; XBP-1 loss increases basal ER stress and PEK-1 activation (richardson2011physiologicalire1xbp1anda pages 138-146, richardson2011physiologicalire1xbp1anda pages 110-118).
- Downstream pathway effects: Global attenuation of translation with selective ISR-driven translation, and regulation of a defined subset of inducible UPR-ER genes; required for ER stress tolerance and for organismal survival in specific stress contexts (richardson2011physiologicalire1xbp1anda pages 110-118, ma2023theintegratedstress pages 1-2).
- Genetic interactions: Synthetic lethality/arrest with impaired ire-1/xbp-1 or atf-6 branches shows complementary essentiality during development; compensatory activation among branches occurs under physiological stress (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 46-48, richardson2011physiologicalire1xbp1anda pages 138-146).
- Phenotypes:
- Development: Double-branch UPR mutants arrest early; neuron-specific PEK-1 activity controls dauer entry via eIF2α phosphorylation (richardson2011physiologicalire1xbp1anda pages 110-118, kulalert2017geneticanalysisof pages 22-26, kulalert2017geneticanalysisof pages 17-22).
- Immunity/physiology: Required to cope with innate immune activation and high temperature; IRE-1/XBP-1 and PEK-1 act in parallel to maintain ER homeostasis under these conditions (richardson2011physiologicalire1xbp1anda pages 138-146).
- Replication stress: pek-1 mutants are sensitized to HU-induced replication stress, with impaired growth and developmental progression; UPR-ER (including PEK-1) protects against replication stress–associated genome instability (xu2024theunfoldedprotein pages 8-9, xu2024theunfoldedprotein pages 9-9, xu2024theunfoldedprotein pages 11-12).
- Subcellular localization: ER-resident type I transmembrane kinase (PERK family topology) (richardson2011investigatingtherole pages 110-118, richardson2011physiologicalire1xbp1anda pages 110-118).

Evidence table
| Aspect | Key finding | Representative quantitative/statistical detail | Year/source label | DOI/URL |
|---|---|---:|---|---|
| Molecular function | PEK-1 is a Ser/Thr eIF2α kinase (C. elegans PERK ortholog) that phosphorylates eIF2α (Ser49) to modulate translation under stress (genetic and biochemical evidence). (kulalert2017geneticanalysisof pages 22-26, richardson2011investigatingtherole pages 110-118) | Phosphorylation site: eIF2α Ser49; genetic phosphomimetic (S49D) and nonphosphorylatable (S49A) constructs produced strong qualitative phenotypic effects in ASI-focused assays. | 2017 (Kulalert et al.), 2011 (Richardson) | n/a |
| Activation context | Activated by ER stress (accumulation of misfolded proteins), immune activation (PMK-1 pathway), and elevated physiological temperatures; basal activity increases when XBP-1 is deficient. (richardson2011physiologicalire1xbp1anda pages 138-146, richardson2011physiologicalire1xbp1anda pages 110-118) | Temperature- and immune-dependent requirement; double mutants show temperature-sensitive synthetic phenotypes (e.g., developmental arrest at elevated temps). | 2011 (Richardson) | https://doi.org/10.1371/journal.pgen.1002391 |
| Downstream effects (ISR/UPR) | Phosphorylation of eIF2α by PEK-1 causes global translational attenuation and activation of the integrated stress response (selective translation of ATF4-like outputs); PEK-1 regulates a subset of inducible UPR genes. (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 46-48) | Microarray evidence: PEK-1 required for induction of ~23% of inducible UPR (i-UPR) genes (reported in UPR profiling studies). | 2005 (Shen et al.), 2011 (Richardson) | https://doi.org/10.1371/journal.pgen.0010037 |
| Cellular localization | PEK-1 is a type I transmembrane ER-resident luminal sensor/kinase (ER membrane localization consistent with PERK family topology). (richardson2011investigatingtherole pages 110-118, richardson2011physiologicalire1xbp1anda pages 110-118) | n/a (membrane topology and ER localization established by homology and functional annotation). | 2011 (Richardson) | https://doi.org/10.1371/journal.pgen.1002391 |
| Genetic interactions | PEK-1 acts partially redundantly with the IRE-1/XBP-1 and ATF-6 branches; combined loss of branches (e.g., ire-1/xbp-1 with pek-1 or atf-6) causes developmental arrest, indicating overlapping essential roles. (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 46-48) | Deletion of ire-1 or xbp-1 is synthetically lethal with deletion of atf-6 or pek-1, producing larval stage 2 arrest in genetic studies. | 2005, 2011 (Shen; Richardson) | https://doi.org/10.1371/journal.pgen.0010037, https://doi.org/10.1371/journal.pgen.1002391 |
| Developmental roles (dauer) | Neuron-specific PEK-1 activation (ASI neurons) phosphorylates eIF2α to promote dauer entry; ASI-specific manipulations of eIF2α phosphorylation state modulate dauer phenotypes, showing cell-autonomous developmental control. (kulalert2017geneticanalysisof pages 22-26, kulalert2017geneticanalysisof pages 17-22) | ASI-specific phosphomimetic eIF2α(S49D) substantially restores dauer in pek-1 mutants, while S49A partially suppresses dauer (qualitative genetic rescue/suppression data). | 2017 (Kulalert et al.) | n/a |
| Immunity / physiology (PMK-1, pathogen, temperature) | PEK-1 is required to protect animals during innate immune activation; PMK-1 (p38 MAPK)–driven immune activity increases ER load and PEK-1 dependence. (richardson2011physiologicalire1xbp1anda pages 138-146, richardson2011investigatingtherole pages 181-188) | Example: pmk-1 mutants show enhanced sensitivity to pathogens and were reported to exhibit 100% larval lethality on Pseudomonas aeruginosa at 27°C in genetic assays. | 2011 (Richardson) | https://doi.org/10.1371/journal.pgen.1002391 |
| Recent (2023) findings | Ma et al. (Dec 2023) report that the integrated stress response (PERK/PEK-1–mediated eIF2α phosphorylation) is critical for protection against ER stress and for translation attenuation under ER stress, but is not required for certain dietary-restriction–linked translational and lifespan changes; combined loss of GCN2 and PERK abolished DR-induced lifespan extension. (ma2023theintegratedstress pages 1-2) | Simultaneous loss of GCN2 and PERK abolished dietary-restriction–induced lifespan extension (qualitative summary from experiments); PERK required for translation attenuation and survival under pharmacologic ER stress. | 2023 (Ma et al.) | https://doi.org/10.3389/fcell.2023.1263344 |

Table: Compact table summarizing molecular function, activation, downstream effects, localization, genetic interactions, developmental and immunity roles, and a key 2023 finding for C. elegans pek-1, with source citations to the extracted context IDs.

Notes on verification and symbol ambiguity
- The sources consistently identify pek-1 as the C. elegans PERK ortholog, an ER-resident eIF2α kinase, aligning with UniProt Q19192 annotations and the protein kinase superfamily classification. No conflicting symbol usage was detected in the gathered literature (richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011investigatingtherole pages 110-118).

Key URLs and publication dates
- Xu et al., G3, Jan 2024 (Advance Access Jan 24, 2024): The UPR-ER (including PEK-1) protects against DNA damage from stalled replication forks. URL: https://doi.org/10.1093/g3journal/jkae017 (xu2024theunfoldedprotein pages 11-12, xu2024theunfoldedprotein pages 9-9, xu2024theunfoldedprotein pages 10-11).
- Ma et al., Frontiers in Cell and Developmental Biology, Dec 14, 2023: ISR protects against ER stress; DR phenotypes decoupled from eIF2α phosphorylation; GCN2+PEK-1 jointly required for DR lifespan extension. URL: https://doi.org/10.3389/fcell.2023.1263344 (ma2023theintegratedstress pages 1-2).
- Richardson et al., PLoS Genetics, Nov 2011: Physiological IRE-1–XBP-1 and PEK-1 signaling in development and immunity; ER homeostasis under physiological stress. URL: https://doi.org/10.1371/journal.pgen.1002391 (richardson2011physiologicalire1xbp1anda pages 138-146).
- Shen et al., PLoS Genetics, Sep 2005: Genetic interactions across UPR-ER branches; PEK-1 contribution to inducible UPR gene induction. URL: https://doi.org/10.1371/journal.pgen.0010037 (richardson2011physiologicalire1xbp1anda pages 110-118).

Limitations and open questions
- Quantitative kinetics of PEK-1 activation and in vivo eIF2α phosphorylation dynamics across tissues remain to be resolved at high temporal resolution in C. elegans. The degree of PEK-1’s eIF2α-independent functions, suggested by DR studies, requires target identification (ma2023theintegratedstress pages 1-2).

Conclusion
C. elegans pek-1 encodes an ER transmembrane eIF2α kinase that initiates the ISR under ER stress. It acts in concert with IRE-1/XBP-1 and ATF-6 to maintain ER homeostasis and ensure development, immunity, and stress resistance. Recent work shows UPR-ER (including PEK-1) also protects against replication stress, and that PEK-1’s roles in physiology may extend beyond canonical eIF2α phosphorylation depending on context (xu2024theunfoldedprotein pages 11-12, xu2024theunfoldedprotein pages 9-9, xu2024theunfoldedprotein pages 10-11, ma2023theintegratedstress pages 1-2, richardson2011physiologicalire1xbp1anda pages 110-118, richardson2011physiologicalire1xbp1anda pages 138-146).

References

(richardson2011physiologicalire1xbp1anda pages 110-118): CE Richardson. Physiological ire-1-xbp-1 and pek-1 signaling in endoplasmic reticulum homeostasis in caenorhabditis elegans. Unknown journal, 2011.
(richardson2011investigatingtherole pages 110-118): CE Richardson. Investigating the role of the caenorhabditis elegans unfolded protein response in immunity and development. Unknown journal, 2011.
(xu2024theunfoldedprotein pages 11-12): Jiaming Xu, Brendil Sabatino, Junran Yan, Glafira Ermakova, Kelsie R S Doering, and Stefan Taubert. The unfolded protein response of the endoplasmic reticulum protects caenorhabditis elegans against dna damage caused by stalled replication forks. G3: Genes|Genomes|Genetics, Jan 2024. URL: https://doi.org/10.1093/g3journal/jkae017, doi:10.1093/g3journal/jkae017. This article has 1 citations.
(xu2024theunfoldedprotein pages 9-9): Jiaming Xu, Brendil Sabatino, Junran Yan, Glafira Ermakova, Kelsie R S Doering, and Stefan Taubert. The unfolded protein response of the endoplasmic reticulum protects caenorhabditis elegans against dna damage caused by stalled replication forks. G3: Genes|Genomes|Genetics, Jan 2024. URL: https://doi.org/10.1093/g3journal/jkae017, doi:10.1093/g3journal/jkae017. This article has 1 citations.
(xu2024theunfoldedprotein pages 4-5): Jiaming Xu, Brendil Sabatino, Junran Yan, Glafira Ermakova, Kelsie R S Doering, and Stefan Taubert. The unfolded protein response of the endoplasmic reticulum protects caenorhabditis elegans against dna damage caused by stalled replication forks. G3: Genes|Genomes|Genetics, Jan 2024. URL: https://doi.org/10.1093/g3journal/jkae017, doi:10.1093/g3journal/jkae017. This article has 1 citations.
(ma2023theintegratedstress pages 1-2): Zhengxin Ma, Jordan Horrocks, Dilawar A. Mir, Matthew Cox, Marissa Ruzga, Jarod Rollins, and Aric N. Rogers. The integrated stress response protects against er stress but is not required for altered translation and lifespan from dietary restriction in caenorhabditis elegans. Frontiers in Cell and Developmental Biology, Dec 2023. URL: https://doi.org/10.3389/fcell.2023.1263344, doi:10.3389/fcell.2023.1263344. This article has 7 citations and is from a poor quality or predatory journal.
(kulalert2017geneticanalysisof pages 22-26): W Kulalert. Genetic analysis of the neuronal integrated stress response in developmental plasticity and organismal physiology of c. elegans. Unknown journal, 2017.
(richardson2011physiologicalire1xbp1anda pages 138-146): CE Richardson. Physiological ire-1-xbp-1 and pek-1 signaling in endoplasmic reticulum homeostasis in caenorhabditis elegans. Unknown journal, 2011.
(xu2024theunfoldedprotein pages 8-9): Jiaming Xu, Brendil Sabatino, Junran Yan, Glafira Ermakova, Kelsie R S Doering, and Stefan Taubert. The unfolded protein response of the endoplasmic reticulum protects caenorhabditis elegans against dna damage caused by stalled replication forks. G3: Genes|Genomes|Genetics, Jan 2024. URL: https://doi.org/10.1093/g3journal/jkae017, doi:10.1093/g3journal/jkae017. This article has 1 citations.
(xu2024theunfoldedprotein pages 1-1): Jiaming Xu, Brendil Sabatino, Junran Yan, Glafira Ermakova, Kelsie R S Doering, and Stefan Taubert. The unfolded protein response of the endoplasmic reticulum protects caenorhabditis elegans against dna damage caused by stalled replication forks. G3: Genes|Genomes|Genetics, Jan 2024. URL: https://doi.org/10.1093/g3journal/jkae017, doi:10.1093/g3journal/jkae017. This article has 1 citations.
(xu2024theunfoldedprotein pages 10-11): Jiaming Xu, Brendil Sabatino, Junran Yan, Glafira Ermakova, Kelsie R S Doering, and Stefan Taubert. The unfolded protein response of the endoplasmic reticulum protects caenorhabditis elegans against dna damage caused by stalled replication forks. G3: Genes|Genomes|Genetics, Jan 2024. URL: https://doi.org/10.1093/g3journal/jkae017, doi:10.1093/g3journal/jkae017. This article has 1 citations.
(kulalert2017geneticanalysisof pages 17-22): W Kulalert. Genetic analysis of the neuronal integrated stress response in developmental plasticity and organismal physiology of c. elegans. Unknown journal, 2017.
(richardson2011investigatingtherole pages 46-48): CE Richardson. Investigating the role of the caenorhabditis elegans unfolded protein response in immunity and development. Unknown journal, 2011.
(richardson2011investigatingtherole pages 181-188): CE Richardson. Investigating the role of the caenorhabditis elegans unfolded protein response in immunity and development. Unknown journal, 2011.

Citations

ma2023theintegratedstress pages 1-2
kulalert2017geneticanalysisof pages 22-26
richardson2011investigatingtherole pages 110-118
xu2024theunfoldedprotein pages 11-12
xu2024theunfoldedprotein pages 9-9
xu2024theunfoldedprotein pages 4-5
xu2024theunfoldedprotein pages 8-9
xu2024theunfoldedprotein pages 1-1
xu2024theunfoldedprotein pages 10-11
kulalert2017geneticanalysisof pages 17-22
richardson2011investigatingtherole pages 46-48
richardson2011investigatingtherole pages 181-188
https://doi.org/10.1093/g3journal/jkae017
https://doi.org/10.3389/fcell.2023.1263344
https://doi.org/10.1093/g3journal/jkae017;
https://doi.org/10.1371/journal.pgen.1002391
https://doi.org/10.1371/journal.pgen.0010037
https://doi.org/10.1371/journal.pgen.0010037,
https://doi.org/10.1093/g3journal/jkae017,
https://doi.org/10.3389/fcell.2023.1263344,

📄 View Raw YAML

id: Q19192
gene_symbol: pek-1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: PEK-1 is the C. elegans ortholog of mammalian PERK (PKR-like ER 
  kinase), a type I transmembrane serine/threonine kinase residing in the ER 
  membrane. Upon ER stress caused by accumulation of unfolded proteins, PEK-1 
  phosphorylates the alpha subunit of eukaryotic translation initiation factor 2
  (eIF2alpha) at Ser49, leading to global attenuation of translation while 
  allowing selective translation of stress-responsive mRNAs. PEK-1 is a critical
  component of the Unfolded Protein Response (UPR) and acts in complementary 
  pathways with IRE-1/XBP-1 and ATF-6 to maintain ER homeostasis. Single pek-1 
  mutants are viable but sensitized to ER stress; combined loss of pek-1 with 
  ire-1/xbp-1 or atf-6 causes larval arrest, demonstrating essential redundancy.
  PEK-1 also protects against replication stress-induced DNA damage and 
  functions in neuron-specific control of dauer entry through ASI neurons.
existing_annotations:
  - term:
      id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PEK-1 is a well-established eIF2alpha kinase. The IBA annotation 
        is consistent with phylogenetic conservation and experimental evidence 
        from C. elegans studies showing that PEK-1 phosphorylates eIF2alpha to 
        attenuate translation during ER stress (PMID:10677345, PMID:11779465, 
        PMID:22125500).
      action: ACCEPT
      reason: This is the core molecular function of PEK-1. Direct evidence from
        expression of C. elegans PEK in yeast demonstrated eIF2alpha 
        hyperphosphorylation (PMID:10677345). The IBA annotation correctly 
        captures the conserved kinase activity at the appropriate level of 
        specificity.
      supported_by:
        - reference_id: PMID:10677345
          supporting_text: Pancreatic eukaryotic initiation factor-2alpha kinase
            (PEK) homologues in humans, Drosophila melanogaster and 
            Caenorhabditis elegans that mediate translational control in 
            response to endoplasmic reticulum stress.
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
        - reference_id: file:worm/pek-1/pek-1-deep-research-falcon.md
          supporting_text: 'model: Edison Scientific Literature'
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Nuclear localization is suggested by phylogenetic inference from 
        mammalian PERK, which can translocate to the nucleus under certain 
        conditions. However, the primary localization of PEK-1 is at the ER 
        membrane as a type I transmembrane protein.
      action: KEEP_AS_NON_CORE
      reason: While PERK family members may have nuclear functions, the core 
        localization and function of PEK-1 is at the ER membrane. This 
        annotation may reflect a secondary or conditional localization rather 
        than the primary site of function. UniProt annotation indicates ER 
        membrane as the primary location.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: The cytoplasmic domain of PEK-1 contains the kinase domain that 
        phosphorylates eIF2alpha in the cytoplasm. This annotation reflects that
        the kinase domain faces the cytoplasm.
      action: ACCEPT
      reason: PEK-1 is a type I transmembrane protein with a large cytoplasmic 
        kinase domain (aa 475-1077 per UniProt). The kinase activity occurs in 
        the cytoplasm where eIF2alpha substrates reside. This is consistent with
        the protein topology.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0006446
      label: regulation of translational initiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PEK-1 regulates translation initiation by phosphorylating 
        eIF2alpha, which is a key step in translational initiation control. This
        is a core biological process for PEK-1.
      action: ACCEPT
      reason: The phosphorylation of eIF2alpha by PEK-1 directly regulates 
        translational initiation. This is consistent with experimental evidence 
        and the conserved function of PERK kinases.
      supported_by:
        - reference_id: PMID:10677345
          supporting_text: Pancreatic eukaryotic initiation factor-2alpha kinase
            (PEK) homologues in humans, Drosophila melanogaster and 
            Caenorhabditis elegans that mediate translational control in 
            response to endoplasmic reticulum stress.
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
  - term:
      id: GO:0017148
      label: negative regulation of translation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: PEK-1 negatively regulates global translation through eIF2alpha 
        phosphorylation, leading to reduced translation initiation and global 
        protein synthesis attenuation during ER stress.
      action: ACCEPT
      reason: This is a direct consequence of PEK-1's eIF2alpha kinase activity.
        Phosphorylation of eIF2alpha leads to global translational repression, 
        which is the primary outcome of PEK-1 activation during stress.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0000166
      label: nucleotide binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: PEK-1 contains an ATP-binding domain typical of protein kinases. 
        This is inferred from UniProt keyword mapping and is consistent with the
        kinase activity.
      action: ACCEPT
      reason: As a protein kinase, PEK-1 requires ATP binding for its catalytic 
        activity. This is a true but generic annotation that follows from the 
        kinase function. The annotation is correct but less informative than the
        more specific ATP binding annotation.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0004672
      label: protein kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000002
    review:
      summary: PEK-1 is a protein kinase that phosphorylates eIF2alpha. This 
        annotation is correct but less specific than the eIF2alpha kinase 
        activity annotation.
      action: ACCEPT
      reason: This is a correct parent term annotation. While less specific than
        GO:0004694 (eIF2alpha kinase activity), it accurately reflects PEK-1's 
        function. The IEA annotation from InterPro correctly identifies the 
        protein kinase domain.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PEK-1 is a serine/threonine kinase that phosphorylates eIF2alpha 
        at a serine residue. This is confirmed by the catalytic activity 
        annotations in UniProt.
      action: ACCEPT
      reason: This annotation correctly specifies PEK-1 as a Ser/Thr kinase. The
        catalytic activity is well-documented for phosphorylation of serine and 
        threonine residues on protein substrates.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0005524
      label: ATP binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: PEK-1 contains an ATP binding site typical of protein kinases, 
        required for its kinase activity.
      action: ACCEPT
      reason: ATP binding is essential for PEK-1 kinase activity. The protein 
        contains conserved ATP binding motifs in the kinase domain.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: PEK-1 is a type I transmembrane protein localized to the ER 
        membrane, where it senses ER stress through its lumenal domain and 
        transmits signals to the cytoplasm.
      action: ACCEPT
      reason: ER membrane localization is the primary and essential localization
        for PEK-1 function. The lumenal domain senses unfolded proteins, 
        triggering oligomerization and activation of the cytoplasmic kinase 
        domain.
      supported_by:
        - reference_id: UniProt:Q19192
        - reference_id: PMID:10677345
          supporting_text: Pancreatic eukaryotic initiation factor-2alpha kinase
            (PEK) homologues in humans, Drosophila melanogaster and 
            Caenorhabditis elegans that mediate translational control in 
            response to endoplasmic reticulum stress.
  - term:
      id: GO:0006417
      label: regulation of translation
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: PEK-1 regulates translation through phosphorylation of eIF2alpha.
        This is a broader parent term for its role in translation regulation.
      action: ACCEPT
      reason: This is a correct but generic annotation. More specific child 
        terms (regulation of translational initiation, negative regulation of 
        translation) are also annotated and provide better specificity.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
  - term:
      id: GO:0006986
      label: response to unfolded protein
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: PEK-1 is activated by accumulation of unfolded proteins in the ER
        lumen and is a core component of the Unfolded Protein Response.
      action: ACCEPT
      reason: This is a fundamental aspect of PEK-1 function. The protein is 
        activated by ER stress caused by unfolded proteins and mediates a key 
        arm of the UPR.
      supported_by:
        - reference_id: PMID:10677345
          supporting_text: Pancreatic eukaryotic initiation factor-2alpha kinase
            (PEK) homologues in humans, Drosophila melanogaster and 
            Caenorhabditis elegans that mediate translational control in 
            response to endoplasmic reticulum stress.
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0016301
      label: kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: PEK-1 has kinase activity, specifically as a serine/threonine 
        protein kinase.
      action: ACCEPT
      reason: This is a correct but very generic parent term. The annotation is 
        accurate but provides less information than the more specific kinase 
        activity terms also annotated.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0016740
      label: transferase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: As a kinase, PEK-1 transfers phosphate groups and thus has 
        transferase activity.
      action: ACCEPT
      reason: This is a correct but extremely generic parent term annotation. 
        All kinases have transferase activity. While accurate, more specific 
        terms provide better functional characterization.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: PEK-1 is activated by ER stress and mediates the translational 
        attenuation arm of the ER stress response.
      action: ACCEPT
      reason: This is a core biological process for PEK-1. The protein is one of
        the three main sensors of ER stress in metazoans and mediates protective
        responses to ER stress.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
        - reference_id: PMID:10677345
          supporting_text: Pancreatic eukaryotic initiation factor-2alpha kinase
            (PEK) homologues in humans, Drosophila melanogaster and 
            Caenorhabditis elegans that mediate translational control in 
            response to endoplasmic reticulum stress.
  - term:
      id: GO:0106310
      label: protein serine kinase activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000116
    review:
      summary: PEK-1 phosphorylates serine residues on protein substrates 
        including eIF2alpha.
      action: ACCEPT
      reason: This annotation correctly identifies PEK-1's serine kinase 
        activity based on the Rhea reaction annotation in UniProt. EIF2alpha is 
        phosphorylated at a serine residue.
      supported_by:
        - reference_id: UniProt:Q19192
  - term:
      id: GO:1904688
      label: regulation of cytoplasmic translational initiation
    evidence_type: IGI
    original_reference_id: PMID:22719267
    review:
      summary: This annotation from PMID:22719267 examines GCN-2 rather than 
        PEK-1 as the primary subject. The paper studies the role of GCN-2 in 
        mitochondrial stress and includes gcn-2;pek-1 double mutants to examine 
        eIF2alpha phosphorylation.
      action: ACCEPT
      reason: The paper demonstrates that PEK-1 and GCN-2 have overlapping roles
        in eIF2alpha phosphorylation and translational regulation. The IGI 
        annotation is appropriate as it shows genetic interaction between pek-1 
        and gcn-2 in regulating cytoplasmic translation initiation.
      additional_reference_ids:
        - PMID:22719267
      supported_by:
        - reference_id: PMID:22719267
          supporting_text: Jun 14. Protective coupling of mitochondrial function
            and protein synthesis via the eIF2α kinase GCN-2.
  - term:
      id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
    evidence_type: IGI
    original_reference_id: PMID:22125500
    review:
      summary: PMID:22125500 (Richardson et al. 2011) demonstrates that XBP-1 
        deficiency increases PEK-1 dependent phosphorylation of eIF2alpha, 
        providing genetic interaction evidence for PEK-1's eIF2alpha kinase 
        activity.
      action: ACCEPT
      reason: This IGI annotation is supported by experimental evidence showing 
        PEK-1-dependent eIF2alpha phosphorylation in xbp-1 mutant backgrounds. 
        The genetic interaction with xbp-1 demonstrates PEK-1's kinase activity 
        in vivo.
      supported_by:
        - reference_id: PMID:22125500
          supporting_text: 2011 Nov 17. Physiological IRE-1-XBP-1 and PEK-1 
            signaling in Caenorhabditis elegans larval development and immunity.
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:22125500
    review:
      summary: PMID:22125500 demonstrates that PEK-1 functions in the ER 
        unfolded protein response alongside IRE-1/XBP-1, with both pathways 
        maintaining ER homeostasis under physiological conditions.
      action: ACCEPT
      reason: This is a core biological process for PEK-1. The IMP evidence is 
        strong, showing that pek-1 mutants have altered ER stress responses and 
        that xbp-1;pek-1 double mutants show synthetic phenotypes indicative of 
        essential UPR function.
      supported_by:
        - reference_id: PMID:22125500
          supporting_text: 2011 Nov 17. Physiological IRE-1-XBP-1 and PEK-1 
            signaling in Caenorhabditis elegans larval development and immunity.
  - term:
      id: GO:0036499
      label: PERK-mediated unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:11779465
    review:
      summary: PMID:11779465 (Shen et al. 2001) established that pek-1 mediates 
        a distinct arm of the UPR through translational attenuation, acting in 
        complementary pathways with IRE-1/XBP-1.
      action: ACCEPT
      reason: This is the most specific and accurate term for PEK-1's role in 
        the UPR. The IMP evidence from this foundational paper demonstrates 
        PEK-1's function in mediating translational attenuation during ER 
        stress.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
  - term:
      id: GO:0036499
      label: PERK-mediated unfolded protein response
    evidence_type: IGI
    original_reference_id: PMID:11779465
    review:
      summary: PMID:11779465 shows genetic interactions between pek-1 and 
        ire-1/xbp-1, demonstrating that PEK-1 acts in a complementary pathway 
        for the UPR.
      action: ACCEPT
      reason: The IGI evidence demonstrates that pek-1 and ire-1/xbp-1 function 
        in complementary pathways, with double mutants showing synthetic 
        developmental defects. This genetic interaction supports PEK-1's role in
        the PERK-mediated UPR.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IMP
    original_reference_id: PMID:11779465
    review:
      summary: PMID:11779465 demonstrates through mutant phenotype analysis that
        PEK-1 functions in the ER UPR.
      action: ACCEPT
      reason: This IMP annotation is well-supported by the mutant phenotype data
        showing that pek-1 mutants are sensitized to ER stress and that combined
        loss of pek-1 with other UPR branches causes developmental arrest.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    evidence_type: IGI
    original_reference_id: PMID:11779465
    review:
      summary: PMID:11779465 demonstrates genetic interactions between pek-1 and
        other UPR components (ire-1, xbp-1) showing that PEK-1 functions in the 
        ER UPR.
      action: ACCEPT
      reason: The IGI evidence from genetic interaction studies with ire-1/xbp-1
        strongly supports PEK-1's role in the ER UPR. Double mutants show 
        synthetic developmental arrest.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
  - term:
      id: GO:0002119
      label: nematode larval development
    evidence_type: IGI
    original_reference_id: PMID:11779465
    review:
      summary: PMID:11779465 shows that pek-1 functions in larval development, 
        with xbp-1;pek-1 or ire-1;pek-1 double mutants arresting at larval 
        stages.
      action: KEEP_AS_NON_CORE
      reason: While pek-1 is required for normal larval development (especially 
        in combination with other UPR mutants), developmental regulation is not 
        the core molecular function of PEK-1. This represents a pleiotropic 
        consequence of its role in ER homeostasis rather than a primary 
        function.
      supported_by:
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
    evidence_type: IDA
    original_reference_id: PMID:10677345
    review:
      summary: PMID:10677345 (Sood et al. 2000) provides direct experimental 
        evidence that C. elegans PEK phosphorylates eIF2alpha when expressed in 
        yeast, inhibiting growth through hyperphosphorylation of eIF2alpha and 
        inhibition of eIF2B.
      action: ACCEPT
      reason: This is the strongest experimental evidence for PEK-1's eIF2alpha 
        kinase activity. The IDA annotation is based on direct assay of the 
        kinase activity in a heterologous yeast system.
      supported_by:
        - reference_id: PMID:10677345
          supporting_text: Pancreatic eukaryotic initiation factor-2alpha kinase
            (PEK) homologues in humans, Drosophila melanogaster and 
            Caenorhabditis elegans that mediate translational control in 
            response to endoplasmic reticulum stress.
  - term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
    evidence_type: ISS
    original_reference_id: PMID:11779465
    review:
      summary: PMID:11779465 supports ER membrane localization based on sequence
        similarity to mammalian PERK, which is established as an ER membrane 
        protein.
      action: ACCEPT
      reason: The ISS annotation is appropriate given the strong sequence 
        conservation with mammalian PERK and the conserved domain architecture 
        including a signal peptide, lumenal domain, transmembrane domain, and 
        cytoplasmic kinase domain.
      supported_by:
        - reference_id: UniProt:Q19192
        - reference_id: PMID:11779465
          supporting_text: Complementary signaling pathways regulate the 
            unfolded protein response and are required for C.
  - term:
      id: GO:0045947
      label: negative regulation of translational initiation
    evidence_type: IC
    original_reference_id: PMID:10677345
    review:
      summary: PMID:10677345 provides the basis for inferring that PEK-1 
        negatively regulates translational initiation through eIF2alpha 
        phosphorylation, which inhibits eIF2B and prevents translation 
        initiation.
      action: ACCEPT
      reason: The IC annotation appropriately captures the logical inference 
        from the demonstrated eIF2alpha kinase activity to its regulatory 
        consequence on translational initiation. Phosphorylated eIF2alpha 
        inhibits eIF2B, preventing GDP-GTP exchange needed for translation 
        initiation.
      supported_by:
        - reference_id: PMID:10677345
          supporting_text: Pancreatic eukaryotic initiation factor-2alpha kinase
            (PEK) homologues in humans, Drosophila melanogaster and 
            Caenorhabditis elegans that mediate translational control in 
            response to endoplasmic reticulum stress.
        - reference_id: UniProt:Q19192
  - term:
      id: GO:0035966
      label: response to topologically incorrect protein
    evidence_type: IMP
    original_reference_id: PMID:23335331
    review:
      summary: PMID:23335331 (Schipanski et al. 2013) uses a C. elegans model of
        FENIB (familial encephalopathy with neuroserpin inclusion bodies) to 
        show that UPR pathways including PEK-1 modulate protein aggregation and 
        respond to misfolded proteins.
      action: ACCEPT
      reason: The annotation captures PEK-1's role in responding to 
        topologically incorrect/misfolded proteins. The paper shows that 
        downregulation of UPR pathways (including pek-1) favors mutant protein 
        accumulation.
      supported_by:
        - reference_id: PMID:23335331
          supporting_text: Jan 18. A novel interaction between aging and ER 
            overload in a protein conformational dementia.
  - term:
      id: GO:0035966
      label: response to topologically incorrect protein
    evidence_type: IGI
    original_reference_id: PMID:23335331
    review:
      summary: PMID:23335331 demonstrates genetic interactions showing that 
        PEK-1 and other UPR components respond to topologically incorrect 
        proteins (aggregating neuroserpin mutants).
      action: ACCEPT
      reason: The IGI annotation reflects genetic interaction evidence where 
        loss of pek-1 in combination with other UPR mutations affects the 
        response to misfolded proteins.
      supported_by:
        - reference_id: PMID:23335331
          supporting_text: Jan 18. A novel interaction between aging and ER 
            overload in a protein conformational dementia.
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: GO_REF:0000116
    title: Automatic Gene Ontology annotation based on Rhea mapping
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10677345
    title: Pancreatic eukaryotic initiation factor-2alpha kinase (PEK) 
      homologues in humans, Drosophila melanogaster and Caenorhabditis elegans 
      that mediate translational control in response to endoplasmic reticulum 
      stress.
    findings:
      - statement: Identified and characterized C. elegans PEK; demonstrated 
          eIF2alpha kinase activity in yeast expression system; showed PEK 
          inhibits translation through eIF2alpha hyperphosphorylation and eIF2B 
          inhibition.
        supporting_text: To address the role of C. elegans PEK in translational 
          control, we expressed this kinase in yeast and found that it inhibits 
          growth by hyperphosphorylation of eIF-2alpha and inhibition of eIF-2B.
  - id: PMID:11779465
    title: Complementary signaling pathways regulate the unfolded protein 
      response and are required for C. elegans development.
    findings:
      - statement: Established that pek-1 mediates translation attenuation arm 
          of UPR; showed pek-1 acts in complementary pathways with ire-1/xbp-1 
          for development and survival; demonstrated synthetic lethality of 
          double UPR mutants.
        supporting_text: In addition, ire-1/xbp-1 acts with pek-1, a protein 
          kinase that mediates translation attenuation, in complementary 
          pathways that are essential for worm development and survival.
  - id: PMID:22125500
    title: Physiological IRE-1-XBP-1 and PEK-1 signaling in Caenorhabditis 
      elegans larval development and immunity.
    findings:
      - statement: Demonstrated increased PEK-1-dependent eIF2alpha 
          phosphorylation in xbp-1 mutants; defined temperature-dependent 
          requirements for XBP-1 and PEK-1; showed both pathways maintain ER 
          homeostasis under physiological conditions including immune 
          activation.
        supporting_text: "XBP-1 deficiency increases PEK-1 dependent phosphorylation
          of eIF2α."
  - id: PMID:22719267
    title: "Protective coupling of mitochondrial function and protein synthesis via
      the eIF2α kinase GCN-2."
    findings:
      - statement: Demonstrated GCN-2 and PEK-1 have overlapping roles in 
          eIF2alpha phosphorylation; showed gcn-2;pek-1 double mutants in 
          context of mitochondrial stress studies.
        supporting_text: "GCN-2, an eIF2α kinase that modulates cytosolic protein
          synthesis, functions in a complementary pathway to that of HAF-1 and ATFS-1."
  - id: PMID:23335331
    title: A novel interaction between aging and ER overload in a protein 
      conformational dementia.
    findings:
      - statement: Used C. elegans FENIB model to show UPR pathways including 
          PEK-1 modulate aggregation of misfolded proteins; downregulation of 
          UPR pathways favors mutant protein accumulation.
        supporting_text: Specifically, downregulation of the unfolded protein 
          response (UPR) pathways in the worm favors mutant SRP-2 accumulation
  - id: file:worm/pek-1/pek-1-deep-research-falcon.md
    title: Deep research report on pek-1
    findings: []
core_functions:
  - molecular_function:
      id: GO:0004694
      label: eukaryotic translation initiation factor 2alpha kinase activity
    description: Direct experimental evidence from PMID:10677345 showing C. 
      elegans PEK phosphorylates eIF2alpha in yeast expression system; supported
      by genetic studies in PMID:11779465 and PMID:22125500 demonstrating 
      PEK-1-dependent eIF2alpha phosphorylation.
proposed_new_terms: []
suggested_questions:
  - question: Does PEK-1 have substrates beyond eIF2alpha in C. elegans? Recent 
      work suggests eIF2alpha-independent functions during dietary restriction. 
      Ma et al. 2023 showed that dietary restriction phenotypes can occur 
      without eIF2alpha phosphorylation, but combined loss of gcn-2 and pek-1 
      abolished DR-induced lifespan extension, suggesting additional substrates 
      or functions.
  - question: What is the tissue-specific expression pattern of PEK-1 beyond 
      intestinal cells? UniProt notes expression in intestinal cells; work on 
      dauer entry shows neuron-specific (ASI) function; comprehensive tissue 
      expression data would be valuable.
suggested_experiments:
  - description: Phosphoproteomics in pek-1 mutants vs wild-type under ER stress
      to identify additional PEK-1 substrates beyond eIF2alpha. Recent evidence 
      suggests eIF2alpha-independent functions of PEK-1; identifying additional 
      substrates would provide mechanistic insight.
  - description: Tissue-specific rescue experiments to determine which tissues 
      require PEK-1 for different stress responses (ER stress, replication 
      stress, immune activation). PEK-1 has been shown to function in intestine 
      and ASI neurons; systematic tissue-specific analysis would define where 
      PEK-1 is required for each stress response.
tags:
  - caeel-upr-stress

pek-1

Gene Description

Existing Annotations Review

Core Functions

Direct experimental evidence from PMID:10677345 showing C. elegans PEK phosphorylates eIF2alpha in yeast expression system; supported by genetic studies in PMID:11779465 and PMID:22125500 demonstrating PEK-1-dependent eIF2alpha phosphorylation.

References

Suggested Questions for Experts

Suggested Experiments

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📚 Additional Documentation

Deep Research Falcon

Question

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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

Research Target:

Output

Gene Research for Functional Annotation

⚠️ CRITICAL: Gene/Protein Identification Context

Target Gene/Protein Identity (from UniProt):

MANDATORY VERIFICATION STEPS:

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

Research Target:

Citations

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