{"gene":"CNOT11","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2012,"finding":"C2ORF29 (CNOT11) is a bona fide subunit of the human CCR4-NOT complex; it interacts with the N-terminal region of CNOT1 and with CNOT10, and is required for the association of CNOT10 with the CCR4-NOT complex, forming a distinct CNOT10/CNOT11 module.","method":"Co-immunoprecipitation, affinity purification of CCR4-NOT complex, knockdown/depletion experiments","journal":"RNA biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and complex purification with functional knockdown demonstrating CNOT10 loss from complex; single lab but multiple orthogonal methods","pmids":["23232451"],"is_preprint":false},{"year":2022,"finding":"High-resolution structural analysis of the human CNOT1-CNOT10-CNOT11 N-terminal module revealed that two helical domains of CNOT1 sandwich CNOT10 and CNOT11, with the most conserved domain of CNOT11 protruding into solvent as an 'antenna' domain. This antenna domain was identified as the binding site for GGNBP2 (a tumor suppressor and spermatogenic factor), establishing the N-terminal module as a protein-protein interaction platform.","method":"X-ray crystallography/cryo-EM structural approaches, biochemical interaction assays (pulldown/co-IP with GGNBP2)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution structure combined with biochemical validation of a novel binding partner, multiple structural approaches in one study","pmids":["36586408"],"is_preprint":false},{"year":2025,"finding":"CNOT11 (together with CNOT1 and CNOT10) is a central effector of tubulin mRNA autoregulation and basal tubulin mRNA stability; siRNA knockdown of CNOT11 impairs rapid tubulin mRNA degradation triggered by elevated soluble tubulin levels.","method":"siRNA knockdown of CNOT11 coupled with Roadblock-qPCR kinetic measurements of tubulin mRNA levels","journal":"microPublication biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean siRNA knockdown with quantitative mRNA decay readout, single lab, single method","pmids":["41426964"],"is_preprint":false},{"year":2026,"finding":"Hepatocyte-specific knockout of Cnot11 in mice causes delayed postnatal hepatocyte maturation (increased Ki67+ HNF4A+ cells, upregulated cell cycle genes, downregulated metabolic genes) and transient liver dysfunction, demonstrating that CNOT11 is required for timely establishment of mature hepatocyte gene expression programs. Global Cnot11 knockout is embryonic lethal, indicating an essential role in early development.","method":"Conditional (hepatocyte-specific) Cnot11 knockout mouse model, histology, Ki67 immunostaining, RNA-seq transcriptomics, serum biochemistry","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vivo with defined phenotypic readouts and transcriptomic analysis; single lab, multiple orthogonal methods","pmids":["42047232"],"is_preprint":false}],"current_model":"CNOT11 (C2ORF29) is a non-catalytic subunit of the mammalian CCR4-NOT deadenylase complex that, together with CNOT10, forms a structural N-terminal module anchored to CNOT1; the conserved 'antenna' domain of CNOT11 serves as a protein-protein interaction platform (e.g., binding GGNBP2), CNOT11 is required for CNOT10 association with the complex, and functionally it acts as a central effector of tubulin mRNA autoregulation and post-transcriptional gene regulation during hepatocyte maturation and early mammalian development."},"narrative":{"mechanistic_narrative":"CNOT11 (C2ORF29) is a non-catalytic subunit of the human CCR4-NOT deadenylase complex that functions in post-transcriptional gene regulation [PMID:23232451]. Together with CNOT10, it forms a distinct module that interacts with the N-terminal region of CNOT1, and CNOT11 is required for the association of CNOT10 with the complex [PMID:23232451]. Structurally, two helical domains of CNOT1 sandwich CNOT10 and CNOT11, while the most conserved domain of CNOT11 protrudes as an 'antenna' domain that serves as a protein-protein interaction platform, binding the tumor suppressor and spermatogenic factor GGNBP2 [PMID:36586408]. Functionally, CNOT11 acts as a central effector of tubulin mRNA autoregulation and basal tubulin mRNA stability, with its depletion impairing rapid tubulin mRNA degradation triggered by elevated soluble tubulin [PMID:41426964]. In vivo, CNOT11 is required for timely establishment of mature hepatocyte gene expression programs, and its global loss is embryonic lethal, indicating an essential developmental role [PMID:42047232].","teleology":[{"year":2012,"claim":"Established that CNOT11 is a genuine subunit of the CCR4-NOT complex and defined its architectural role, resolving how the CNOT10/CNOT11 module attaches to the deadenylase machinery.","evidence":"Co-immunoprecipitation, affinity purification of CCR4-NOT, and knockdown/depletion in human cells","pmids":["23232451"],"confidence":"High","gaps":["No structural detail on how the module docks onto CNOT1","Molecular function of the module within deadenylation left undefined","No mRNA targets identified"]},{"year":2022,"claim":"Defined the structural basis of the N-terminal module and revealed that CNOT11's conserved 'antenna' domain is a protein-protein interaction surface, providing a mechanistic role beyond mere scaffolding.","evidence":"High-resolution structural analysis of the CNOT1-CNOT10-CNOT11 module with biochemical validation of GGNBP2 binding","pmids":["36586408"],"confidence":"High","gaps":["Functional consequence of GGNBP2 recruitment to the complex not established","Whether the antenna domain binds additional partners unknown","Link between antenna-mediated interactions and target mRNA selection not shown"]},{"year":2025,"claim":"Connected CNOT11 to a specific regulatory output by showing it is required for tubulin mRNA autoregulation and basal stability, demonstrating the module participates in target-specific mRNA decay.","evidence":"siRNA knockdown of CNOT11 with Roadblock-qPCR kinetic measurement of tubulin mRNA decay in human cells","pmids":["41426964"],"confidence":"Medium","gaps":["Single lab, single method without orthogonal validation","Mechanism by which the module senses soluble tubulin to trigger decay not resolved","Whether CNOT11 directly contacts the target mRNA or recruits a sensing factor unknown"]},{"year":2026,"claim":"Demonstrated the physiological requirement for CNOT11 in mammalian development and organ maturation, showing the gene is essential and shapes hepatocyte gene expression programs.","evidence":"Hepatocyte-specific and global Cnot11 knockout mouse models with histology, Ki67 immunostaining, RNA-seq, and serum biochemistry","pmids":["42047232"],"confidence":"Medium","gaps":["Direct mRNA targets driving the maturation phenotype not identified","Stage of embryonic lethality and underlying cause not defined","Connection between hepatocyte phenotype and deadenylase activity not mechanistically traced"]},{"year":null,"claim":"How CNOT11 directs target-specific mRNA selection and how its antenna-domain interactions translate into the developmental and maturation programs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No genome-wide map of CNOT11-dependent mRNA targets","Functional role of GGNBP2 recruitment in mRNA decay undefined","Mechanistic link between the antenna platform and physiological phenotypes missing"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,2]}],"complexes":["CCR4-NOT","CNOT1-CNOT10-CNOT11 N-terminal module"],"partners":["CNOT1","CNOT10","GGNBP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKZ1","full_name":"CCR4-NOT transcription complex subunit 11","aliases":[],"length_aa":510,"mass_kda":55.2,"function":"Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Is required for the association of CNOT10 with the CCR4-NOT complex. Does not seem to be required for complex deadenylase function","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UKZ1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CNOT11","classification":"Not Classified","n_dependent_lines":165,"n_total_lines":1208,"dependency_fraction":0.13658940397350994},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"G3BP2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CNOT11","total_profiled":1310},"omim":[{"mim_id":"620509","title":"CCR4-NOT TRANSCRIPTION COMPLEX, SUBUNIT 11; CNOT11","url":"https://www.omim.org/entry/620509"},{"mim_id":"620508","title":"CCR4-NOT TRANSCRIPTION COMPLEX, SUBUNIT 10; CNOT10","url":"https://www.omim.org/entry/620508"}],"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/CNOT11"},"hgnc":{"alias_symbol":["C40"],"prev_symbol":["C2orf29"]},"alphafold":{"accession":"Q9UKZ1","domains":[{"cath_id":"-","chopping":"66-156_171-246_256-281","consensus_level":"high","plddt":88.1765,"start":66,"end":281}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKZ1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKZ1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKZ1-F1-predicted_aligned_error_v6.png","plddt_mean":76.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CNOT11","jax_strain_url":"https://www.jax.org/strain/search?query=CNOT11"},"sequence":{"accession":"Q9UKZ1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKZ1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKZ1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKZ1"}},"corpus_meta":[{"pmid":"1935909","id":"PMC_1935909","title":"AppppA binds to 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diapophytoene and related desaturases of C(30) and C(40) carotenoid biosynthetic pathways.","date":"2001","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/11566453","citation_count":36,"is_preprint":false},{"pmid":"17261513","id":"PMC_17261513","title":"Use of transposon promoter-probe vectors in the metabolic engineering of the obligate methanotroph Methylomonas sp. strain 16a for enhanced C40 carotenoid synthesis.","date":"2007","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17261513","citation_count":30,"is_preprint":false},{"pmid":"17257797","id":"PMC_17257797","title":"Progress on molecular breeding and metabolic engineering of biosynthesis pathways of C(30), C(35), C(40), C(45), C(50) carotenoids.","date":"2006","source":"Biotechnology advances","url":"https://pubmed.ncbi.nlm.nih.gov/17257797","citation_count":29,"is_preprint":false},{"pmid":"28567628","id":"PMC_28567628","title":"Enzyme-mediated biodegradation of long-chain n-alkanes (C32 and C40) by thermophilic bacteria.","date":"2017","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/28567628","citation_count":23,"is_preprint":false},{"pmid":"17371049","id":"PMC_17371049","title":"Comparison of C40/82A and P27A C40/82A barstar mutants using 19F NMR.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17371049","citation_count":22,"is_preprint":false},{"pmid":"36586408","id":"PMC_36586408","title":"The human CNOT1-CNOT10-CNOT11 complex forms a structural platform for protein-protein interactions.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36586408","citation_count":21,"is_preprint":false},{"pmid":"38582923","id":"PMC_38582923","title":"Enhancing astaxanthin biosynthesis and pathway expansion towards glycosylated C40 carotenoids by Corynebacterium glutamicum.","date":"2024","source":"Scientific 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Supplement","url":"https://pubmed.ncbi.nlm.nih.gov/8933090","citation_count":0,"is_preprint":false},{"pmid":"2788461","id":"PMC_2788461","title":"[The role of the state of protein-lipid interactions in stimulated membranes in the conformation of C40-carotenoids].","date":"1989","source":"Biofizika","url":"https://pubmed.ncbi.nlm.nih.gov/2788461","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14259,"output_tokens":1144,"usd":0.029968,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7730,"output_tokens":1866,"usd":0.04265,"stage2_stop_reason":"end_turn"},"total_usd":0.072618,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"C2ORF29 (CNOT11) is a bona fide subunit of the human CCR4-NOT complex; it interacts with the N-terminal region of CNOT1 and with CNOT10, and is required for the association of CNOT10 with the CCR4-NOT complex, forming a distinct CNOT10/CNOT11 module.\",\n      \"method\": \"Co-immunoprecipitation, affinity purification of CCR4-NOT complex, knockdown/depletion experiments\",\n      \"journal\": \"RNA biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and complex purification with functional knockdown demonstrating CNOT10 loss from complex; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23232451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"High-resolution structural analysis of the human CNOT1-CNOT10-CNOT11 N-terminal module revealed that two helical domains of CNOT1 sandwich CNOT10 and CNOT11, with the most conserved domain of CNOT11 protruding into solvent as an 'antenna' domain. This antenna domain was identified as the binding site for GGNBP2 (a tumor suppressor and spermatogenic factor), establishing the N-terminal module as a protein-protein interaction platform.\",\n      \"method\": \"X-ray crystallography/cryo-EM structural approaches, biochemical interaction assays (pulldown/co-IP with GGNBP2)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution structure combined with biochemical validation of a novel binding partner, multiple structural approaches in one study\",\n      \"pmids\": [\"36586408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CNOT11 (together with CNOT1 and CNOT10) is a central effector of tubulin mRNA autoregulation and basal tubulin mRNA stability; siRNA knockdown of CNOT11 impairs rapid tubulin mRNA degradation triggered by elevated soluble tubulin levels.\",\n      \"method\": \"siRNA knockdown of CNOT11 coupled with Roadblock-qPCR kinetic measurements of tubulin mRNA levels\",\n      \"journal\": \"microPublication biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean siRNA knockdown with quantitative mRNA decay readout, single lab, single method\",\n      \"pmids\": [\"41426964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Hepatocyte-specific knockout of Cnot11 in mice causes delayed postnatal hepatocyte maturation (increased Ki67+ HNF4A+ cells, upregulated cell cycle genes, downregulated metabolic genes) and transient liver dysfunction, demonstrating that CNOT11 is required for timely establishment of mature hepatocyte gene expression programs. Global Cnot11 knockout is embryonic lethal, indicating an essential role in early development.\",\n      \"method\": \"Conditional (hepatocyte-specific) Cnot11 knockout mouse model, histology, Ki67 immunostaining, RNA-seq transcriptomics, serum biochemistry\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vivo with defined phenotypic readouts and transcriptomic analysis; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42047232\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CNOT11 (C2ORF29) is a non-catalytic subunit of the mammalian CCR4-NOT deadenylase complex that, together with CNOT10, forms a structural N-terminal module anchored to CNOT1; the conserved 'antenna' domain of CNOT11 serves as a protein-protein interaction platform (e.g., binding GGNBP2), CNOT11 is required for CNOT10 association with the complex, and functionally it acts as a central effector of tubulin mRNA autoregulation and post-transcriptional gene regulation during hepatocyte maturation and early mammalian development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CNOT11 (C2ORF29) is a non-catalytic subunit of the human CCR4-NOT deadenylase complex that functions in post-transcriptional gene regulation [#0]. Together with CNOT10, it forms a distinct module that interacts with the N-terminal region of CNOT1, and CNOT11 is required for the association of CNOT10 with the complex [#0]. Structurally, two helical domains of CNOT1 sandwich CNOT10 and CNOT11, while the most conserved domain of CNOT11 protrudes as an 'antenna' domain that serves as a protein-protein interaction platform, binding the tumor suppressor and spermatogenic factor GGNBP2 [#1]. Functionally, CNOT11 acts as a central effector of tubulin mRNA autoregulation and basal tubulin mRNA stability, with its depletion impairing rapid tubulin mRNA degradation triggered by elevated soluble tubulin [#2]. In vivo, CNOT11 is required for timely establishment of mature hepatocyte gene expression programs, and its global loss is embryonic lethal, indicating an essential developmental role [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Established that CNOT11 is a genuine subunit of the CCR4-NOT complex and defined its architectural role, resolving how the CNOT10/CNOT11 module attaches to the deadenylase machinery.\",\n      \"evidence\": \"Co-immunoprecipitation, affinity purification of CCR4-NOT, and knockdown/depletion in human cells\",\n      \"pmids\": [\"23232451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural detail on how the module docks onto CNOT1\",\n        \"Molecular function of the module within deadenylation left undefined\",\n        \"No mRNA targets identified\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined the structural basis of the N-terminal module and revealed that CNOT11's conserved 'antenna' domain is a protein-protein interaction surface, providing a mechanistic role beyond mere scaffolding.\",\n      \"evidence\": \"High-resolution structural analysis of the CNOT1-CNOT10-CNOT11 module with biochemical validation of GGNBP2 binding\",\n      \"pmids\": [\"36586408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of GGNBP2 recruitment to the complex not established\",\n        \"Whether the antenna domain binds additional partners unknown\",\n        \"Link between antenna-mediated interactions and target mRNA selection not shown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected CNOT11 to a specific regulatory output by showing it is required for tubulin mRNA autoregulation and basal stability, demonstrating the module participates in target-specific mRNA decay.\",\n      \"evidence\": \"siRNA knockdown of CNOT11 with Roadblock-qPCR kinetic measurement of tubulin mRNA decay in human cells\",\n      \"pmids\": [\"41426964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab, single method without orthogonal validation\",\n        \"Mechanism by which the module senses soluble tubulin to trigger decay not resolved\",\n        \"Whether CNOT11 directly contacts the target mRNA or recruits a sensing factor unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated the physiological requirement for CNOT11 in mammalian development and organ maturation, showing the gene is essential and shapes hepatocyte gene expression programs.\",\n      \"evidence\": \"Hepatocyte-specific and global Cnot11 knockout mouse models with histology, Ki67 immunostaining, RNA-seq, and serum biochemistry\",\n      \"pmids\": [\"42047232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mRNA targets driving the maturation phenotype not identified\",\n        \"Stage of embryonic lethality and underlying cause not defined\",\n        \"Connection between hepatocyte phenotype and deadenylase activity not mechanistically traced\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CNOT11 directs target-specific mRNA selection and how its antenna-domain interactions translate into the developmental and maturation programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No genome-wide map of CNOT11-dependent mRNA targets\",\n        \"Functional role of GGNBP2 recruitment in mRNA decay undefined\",\n        \"Mechanistic link between the antenna platform and physiological phenotypes missing\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"CCR4-NOT\", \"CNOT1-CNOT10-CNOT11 N-terminal module\"],\n    \"partners\": [\"CNOT1\", \"CNOT10\", \"GGNBP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}