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 or xbp-1 causes L2 larval arrest, and PEK-1 acts synergistically with ATF-6 to complement the developmental requirement for IRE-1/XBP-1. PEK-1 also protects against replication stress-induced DNA damage and functions in neuron-specific control of dauer entry through ASI neurons.
| 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 eIF2Ξ± 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. |
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Download this section (compressed HTML)Q: 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.
Q: 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.
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.
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Download this section (compressed HTML)pek-1 encodes a predicted transmembrane protein kinase orthologous to human eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3, OMIM:604032), which when mutated leads to Wolcott-Rallison syndrome; PEK-1 is strongly expressed in intestinal cells and is required for the unfolded protein response (UPR) that counteracts cellular stress induced by accumulation of unfolded proteins in the endoplasmic reticulum (ER); PEK-1 may function in the endoplasmic reticulum to phosphorylate eIF2alpha and inhibit protein synthesis in response to endogenous ER stress.
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