{"gene":"KLHDC10","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2012,"finding":"KLHDC10 (mammalian ortholog of Drosophila Slim) interacts with Protein phosphatase 5 (PP5) by binding to the phosphatase domain of PP5 and suppressing its phosphatase activity, thereby enabling sustained ROS-induced activation of ASK1 and promoting oxidative stress-induced cell death.","method":"Proteomics screen, Co-IP, in vitro phosphatase activity assay, Drosophila misexpression screen, siRNA knockdown in Neuro2A cells","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, in vitro enzymatic assay, genetic screen, and functional KD with defined phenotypic readout; multiple orthogonal methods in a single study","pmids":["23102700"],"is_preprint":false},{"year":2016,"finding":"KLHDC10 deficiency selectively enhances necroptosis in inflammatory cells encountering DAMPs, reducing the inflammatory cytokine response in TNFα-induced systemic inflammatory response syndrome (SIRS) in mice, without affecting early systemic necroptosis.","method":"KLHDC10 knockout mouse model, TNFα-induced SIRS model, in vitro cell death assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype in vivo and in vitro; single lab study","pmids":["27631783"],"is_preprint":false},{"year":2023,"finding":"KLHDC10, as part of the CRL2-KLHDC10 E3 ligase complex, directly binds C-terminal polyalanine (Ala-tail) degrons generated during ribosome-associated quality control (RQC) of stalled translation products; the Ala-tail-binding pocket of KLHDC10 was structurally predicted and experimentally validated, and this recognition element evolved by tinkering of a widespread C-degron-recognition module.","method":"Biochemical binding assays, in silico structural prediction with experimental validation, mutagenesis of candidate pocket residues, evolutionary sequence analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding assays, structure-guided mutagenesis, and evolutionary validation; multiple orthogonal approaches in single study","pmids":["37676773"],"is_preprint":false}],"current_model":"KLHDC10 is a kelch-repeat protein that functions as an activator of the pro-apoptotic kinase ASK1 by directly binding to the phosphatase domain of PP5 and inhibiting its phosphatase activity, thereby sustaining ROS-induced ASK1 activation; additionally, as the substrate receptor of the CRL2-KLHDC10 E3 ubiquitin ligase complex, it directly recognizes C-terminal polyalanine (Ala-tail) degrons on aberrant nascent polypeptides produced during interrupted translation in ribosome-associated quality control, targeting them for ubiquitylation and degradation."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing KLHDC10 as a regulator of stress-induced apoptosis resolved how ROS-activated ASK1 signaling is sustained: KLHDC10 directly binds and inhibits PP5 phosphatase activity, preventing PP5-mediated dephosphorylation and inactivation of ASK1.","evidence":"Proteomics screen, reciprocal Co-IP, in vitro phosphatase assay, Drosophila genetic screen, and siRNA knockdown in mammalian Neuro2A cells","pmids":["23102700"],"confidence":"High","gaps":["Structural basis of KLHDC10–PP5 interaction not determined","Whether KLHDC10 regulates PP5 substrates beyond ASK1 is unknown","Physiological relevance in mammalian tissues in vivo not established in this study"]},{"year":2016,"claim":"Extending KLHDC10 function in vivo, knockout mice revealed that KLHDC10 deficiency selectively enhances necroptosis in inflammatory cells during TNFα-induced SIRS, dampening the cytokine response — demonstrating a role in modulating inflammatory cell death distinct from its ASK1-apoptosis axis.","evidence":"KLHDC10 knockout mouse model with TNFα-induced systemic inflammatory response syndrome and in vitro cell death assays","pmids":["27631783"],"confidence":"Medium","gaps":["Molecular mechanism linking KLHDC10 to necroptosis pathway components (e.g., RIPK1/RIPK3/MLKL) not identified","Single-lab study; independent replication in additional inflammatory models lacking","Whether PP5 inhibition mediates the necroptosis phenotype was not tested"]},{"year":2023,"claim":"Identification of KLHDC10 as the CRL2 substrate receptor for C-terminal polyalanine degrons established its role in ribosome-associated quality control — a function mechanistically distinct from its PP5 inhibition — and showed that the Ala-tail binding pocket evolved by repurposing a conserved C-degron recognition module.","evidence":"Biochemical binding assays, structure-guided mutagenesis of predicted Ala-tail binding pocket, and evolutionary sequence analysis","pmids":["37676773"],"confidence":"High","gaps":["High-resolution experimental structure of KLHDC10 bound to an Ala-tail substrate not yet available","In vivo contribution of KLHDC10-mediated Ala-tail ubiquitylation to RQC pathway flux not quantified","Relationship between the two known functions (PP5 inhibition vs. CRL2 substrate receptor) is unresolved"]},{"year":null,"claim":"It remains unknown how the dual functions of KLHDC10 — PP5 inhibition in stress signaling and CRL2-mediated ubiquitylation in ribosome quality control — are coordinated or independently regulated in different cellular contexts.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data resolving whether PP5-binding and CRL2-adaptor surfaces overlap","Tissue-specific regulation of the two functions is uncharacterized","Mechanism linking KLHDC10 to necroptosis at the molecular level remains unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,1]}],"complexes":["CRL2-KLHDC10"],"partners":["PP5","ASK1","CUL2"],"other_free_text":[]},"mechanistic_narrative":"KLHDC10 is a kelch-repeat protein that functions both as an inhibitor of protein phosphatase 5 (PP5) and as a substrate receptor in the CRL2 E3 ubiquitin ligase complex. It binds the phosphatase domain of PP5 and suppresses its activity, thereby sustaining ROS-induced activation of the pro-apoptotic kinase ASK1 and promoting oxidative stress-induced cell death [PMID:23102700]. As the substrate-recognition subunit of CRL2-KLHDC10, it directly recognizes C-terminal polyalanine (Ala-tail) degrons on aberrant nascent polypeptides produced during ribosome-associated quality control (RQC), targeting them for ubiquitylation and proteasomal degradation [PMID:37676773]."},"prefetch_data":{"uniprot":{"accession":"Q6PID8","full_name":"Kelch domain-containing protein 10","aliases":[],"length_aa":442,"mass_kda":49.1,"function":"Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C-terminus of target proteins, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:33909987). The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms (PubMed:29779948, PubMed:33909987, PubMed:39548056). The CRL2(KLHDC10) complex specifically recognizes proteins with a proline-glycine (Pro-Gly) or an alanine tail (CAT tail) at the C-terminus, leading to their ubiquitination and degradation (PubMed:29779948, PubMed:33909987). The CRL2(KLHDC10) complex is involved in the ribosome-associated quality control (RQC) pathway, which mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes: CRL2(KLHDC10) acts downstream of NEMF and recognizes CAT tails associated with stalled nascent chains, leading to their ubiquitination and degradation (PubMed:33909987). Participates in the oxidative stress-induced cell death through MAP3K5 activation (PubMed:23102700). Inhibits PPP5C phosphatase activity on MAP3K5 (PubMed:23102700). Acts as a regulator of necroptosis (By similarity)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q6PID8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KLHDC10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/KLHDC10","total_profiled":1310},"omim":[{"mim_id":"615152","title":"KELCH DOMAIN-CONTAINING PROTEIN 10; KLHDC10","url":"https://www.omim.org/entry/615152"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KLHDC10"},"hgnc":{"alias_symbol":["KIAA0265","slim"],"prev_symbol":[]},"alphafold":{"accession":"Q6PID8","domains":[{"cath_id":"2.120.10.80","chopping":"249-359","consensus_level":"medium","plddt":97.3612,"start":249,"end":359},{"cath_id":"-","chopping":"404-442","consensus_level":"medium","plddt":94.889,"start":404,"end":442}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PID8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PID8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PID8-F1-predicted_aligned_error_v6.png","plddt_mean":84.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KLHDC10","jax_strain_url":"https://www.jax.org/strain/search?query=KLHDC10"},"sequence":{"accession":"Q6PID8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PID8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PID8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PID8"}},"corpus_meta":[{"pmid":"30407594","id":"PMC_30407594","title":"PANTHER 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misexpression screen, siRNA knockdown in Neuro2A cells\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, in vitro enzymatic assay, genetic screen, and functional KD with defined phenotypic readout; multiple orthogonal methods in a single study\",\n      \"pmids\": [\"23102700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KLHDC10 deficiency selectively enhances necroptosis in inflammatory cells encountering DAMPs, reducing the inflammatory cytokine response in TNFα-induced systemic inflammatory response syndrome (SIRS) in mice, without affecting early systemic necroptosis.\",\n      \"method\": \"KLHDC10 knockout mouse model, TNFα-induced SIRS model, in vitro cell death assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype in vivo and in vitro; single lab study\",\n      \"pmids\": [\"27631783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"KLHDC10, as part of the CRL2-KLHDC10 E3 ligase complex, directly binds C-terminal polyalanine (Ala-tail) degrons generated during ribosome-associated quality control (RQC) of stalled translation products; the Ala-tail-binding pocket of KLHDC10 was structurally predicted and experimentally validated, and this recognition element evolved by tinkering of a widespread C-degron-recognition module.\",\n      \"method\": \"Biochemical binding assays, in silico structural prediction with experimental validation, mutagenesis of candidate pocket residues, evolutionary sequence analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding assays, structure-guided mutagenesis, and evolutionary validation; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"37676773\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KLHDC10 is a kelch-repeat protein that functions as an activator of the pro-apoptotic kinase ASK1 by directly binding to the phosphatase domain of PP5 and inhibiting its phosphatase activity, thereby sustaining ROS-induced ASK1 activation; additionally, as the substrate receptor of the CRL2-KLHDC10 E3 ubiquitin ligase complex, it directly recognizes C-terminal polyalanine (Ala-tail) degrons on aberrant nascent polypeptides produced during interrupted translation in ribosome-associated quality control, targeting them for ubiquitylation and degradation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"KLHDC10 is a kelch-repeat protein that functions both as an inhibitor of protein phosphatase 5 (PP5) and as a substrate receptor in the CRL2 E3 ubiquitin ligase complex. It binds the phosphatase domain of PP5 and suppresses its activity, thereby sustaining ROS-induced activation of the pro-apoptotic kinase ASK1 and promoting oxidative stress-induced cell death [PMID:23102700]. As the substrate-recognition subunit of CRL2-KLHDC10, it directly recognizes C-terminal polyalanine (Ala-tail) degrons on aberrant nascent polypeptides produced during ribosome-associated quality control (RQC), targeting them for ubiquitylation and proteasomal degradation [PMID:37676773].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing KLHDC10 as a regulator of stress-induced apoptosis resolved how ROS-activated ASK1 signaling is sustained: KLHDC10 directly binds and inhibits PP5 phosphatase activity, preventing PP5-mediated dephosphorylation and inactivation of ASK1.\",\n      \"evidence\": \"Proteomics screen, reciprocal Co-IP, in vitro phosphatase assay, Drosophila genetic screen, and siRNA knockdown in mammalian Neuro2A cells\",\n      \"pmids\": [\"23102700\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of KLHDC10–PP5 interaction not determined\",\n        \"Whether KLHDC10 regulates PP5 substrates beyond ASK1 is unknown\",\n        \"Physiological relevance in mammalian tissues in vivo not established in this study\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extending KLHDC10 function in vivo, knockout mice revealed that KLHDC10 deficiency selectively enhances necroptosis in inflammatory cells during TNFα-induced SIRS, dampening the cytokine response — demonstrating a role in modulating inflammatory cell death distinct from its ASK1-apoptosis axis.\",\n      \"evidence\": \"KLHDC10 knockout mouse model with TNFα-induced systemic inflammatory response syndrome and in vitro cell death assays\",\n      \"pmids\": [\"27631783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism linking KLHDC10 to necroptosis pathway components (e.g., RIPK1/RIPK3/MLKL) not identified\",\n        \"Single-lab study; independent replication in additional inflammatory models lacking\",\n        \"Whether PP5 inhibition mediates the necroptosis phenotype was not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of KLHDC10 as the CRL2 substrate receptor for C-terminal polyalanine degrons established its role in ribosome-associated quality control — a function mechanistically distinct from its PP5 inhibition — and showed that the Ala-tail binding pocket evolved by repurposing a conserved C-degron recognition module.\",\n      \"evidence\": \"Biochemical binding assays, structure-guided mutagenesis of predicted Ala-tail binding pocket, and evolutionary sequence analysis\",\n      \"pmids\": [\"37676773\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"High-resolution experimental structure of KLHDC10 bound to an Ala-tail substrate not yet available\",\n        \"In vivo contribution of KLHDC10-mediated Ala-tail ubiquitylation to RQC pathway flux not quantified\",\n        \"Relationship between the two known functions (PP5 inhibition vs. CRL2 substrate receptor) is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how the dual functions of KLHDC10 — PP5 inhibition in stress signaling and CRL2-mediated ubiquitylation in ribosome quality control — are coordinated or independently regulated in different cellular contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data resolving whether PP5-binding and CRL2-adaptor surfaces overlap\",\n        \"Tissue-specific regulation of the two functions is uncharacterized\",\n        \"Mechanism linking KLHDC10 to necroptosis at the molecular level remains unidentified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\n      \"CRL2-KLHDC10\"\n    ],\n    \"partners\": [\n      \"PP5\",\n      \"ASK1\",\n      \"CUL2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}