{"gene":"KRI1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2000,"finding":"Yeast Kri1p physically interacts with Krr1p (co-immunoprecipitation of myc-tagged Kri1p with HA-tagged Krr1p), localizes to the nucleolus, and both proteins are required for 40S ribosome biogenesis; depletion of Kri1p abolishes 18S rRNA production while 25S rRNA levels remain normal.","method":"Co-immunoprecipitation, nucleolar localization by tagged protein, polysome profiling, pulse-chase rRNA analysis, Northern blot, galactose-shutoff depletion strain","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods (localization, polysome profiling, pulse-chase, Northern), and genetic depletion with specific rRNA processing phenotype in a single rigorous study","pmids":["11027267"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of Krr1 shows it comprises two KH domains (KH1 and KH2); KH1 is a divergent domain lacking the RNA-binding GXXG motif and is the domain responsible for binding Kri1, while KH2 contains a canonical RNA-binding surface and binds Faf1. Disruption of the Krr1-Faf1 interaction (not directly Kri1) impairs early 18S rRNA processing at sites A0, A1, and A2.","method":"Co-crystal structure at 2.8 Å resolution, mutagenesis of interaction surfaces, 18S rRNA processing assays, cell lethality assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — co-crystal structure with functional mutagenesis and rRNA processing readout, multiple orthogonal methods in one rigorous study","pmids":["24990943"],"is_preprint":false},{"year":2025,"finding":"In yeast 90S pre-ribosome assembly, Kri1 is recruited together with Krr1 and Utp23 to a pre-18S rRNA subdomain (platform helices and ES6) chaperoned by the snR30 snoRNP; Krr1-dependent release of snR30 is required for integration of the platform subdomain into the 90S pre-ribosome.","method":"Cryo-EM structural analysis of 90S pre-ribosome intermediates, RNA hybridization blocking experiments, assembly factor recruitment assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with functional validation of snR30 release and platform integration, single lab but multiple orthogonal structural and biochemical methods","pmids":["40399280"],"is_preprint":false},{"year":2006,"finding":"C. elegans kri-1 acts in the intestine to promote DAF-16/FOXO nuclear localization in response to lipophilic-hormone signaling from the germline; kri-1 is required for germ-cell-loss-induced lifespan extension but not for lifespan extension downstream of reduced insulin/IGF-1 signaling.","method":"Genetic epistasis, DAF-16::GFP nuclear localization imaging, lifespan assays in kri-1 mutants and tissue-specific rescue","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with direct subcellular localization readout, pathway placement established with tissue-specific rescue, replicated in multiple genetic backgrounds","pmids":["16530050"],"is_preprint":false},{"year":2010,"finding":"C. elegans kri-1 regulates DNA damage-induced germ cell apoptosis in a cell-nonautonomous manner, independently of cep-1/p53; kri-1 acts in nondying (somatic) cells to promote apoptosis in the germline.","method":"Loss-of-function genetics, tissue-specific rescue, epistasis with cep-1/p53 and core apoptosis pathway genes (ced-4, ced-3), germline apoptosis assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with cell-autonomous vs. non-autonomous rescue experiments and multiple pathway placements, single lab but multiple orthogonal genetic methods","pmids":["20137949"],"is_preprint":false},{"year":2019,"finding":"C. elegans KRI-1 forms a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway, thereby allowing the KLF-3 transcription factor to drive expression of the SLC39 zinc transporter zipt-2.3, which sequesters zinc in the intestine; loss of KRI-1 reduces intestinal zinc sequestration and inhibits IR-induced MPK-1/ERK1 activation and germline apoptosis.","method":"Co-immunoprecipitation (KRI-1/CCM-2 complex), genetic epistasis (kri-1, ccm-2, klf-3, zipt-2.3), zinc localization imaging (in C. elegans and krit1-/- zebrafish), germline apoptosis assay, ERK pathway activation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex, multiple orthogonal genetic epistasis experiments, cross-species validation in zebrafish, and patient tissue data","pmids":["30996251"],"is_preprint":false},{"year":2016,"finding":"C. elegans KRI-1 plays a key role in generating H2S and reactive oxygen species (ROS) downstream of germline loss; kri-1-dependent H2S production activates SKN-1/Nrf2, and kri-1-dependent ROS activate the mitochondrial unfolded-protein response, both contributing to lifespan extension.","method":"Genetic loss-of-function, H2S and ROS measurement in specific tissues, mitochondrial biogenesis assays, epistasis with skn-1 and mitochondrial UPR pathway genes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical measurement of H2S and ROS combined with genetic epistasis and multiple orthogonal pathway readouts, single lab but strong evidence quality","pmids":["27140632"],"is_preprint":false},{"year":2013,"finding":"C. elegans DLC-1 (dynein light chain 1) functions cell-nonautonomously in the same pathway as kri-1 in response to ionizing radiation-induced apoptosis, and DLC-1 regulates the protein levels of KRI-1.","method":"RNAi knockdown, genetic epistasis, KRI-1 protein level measurement, germline apoptosis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic epistasis and protein level measurement, single lab, limited mechanistic depth for KRI-1 specifically","pmids":["24030151"],"is_preprint":false},{"year":2016,"finding":"Inactivation of nhr-49/PPARα in C. elegans causes striking membrane localization of KRI-1, suggesting KRI-1 subcellular localization is regulated by NHR-49 and may operate in a positive feedback loop to potentiate DAF-16/FOXO and TCER-1 activity.","method":"KRI-1 subcellular localization imaging after nhr-49 RNAi, genetic interaction analysis","journal":"Worm","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization observation after RNAi, single lab, no functional rescue or mechanistic follow-up confirming the feedback loop","pmids":["27073739"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, KRI-1 is required for paraquat-induced activation of SKN-1/Nrf2 and consequent collagen gene transcription; in human lung fibroblasts (MRC-5), both KRIT1 and Nrf2 are required for collagen transcription in response to paraquat, and KEAP1 knockdown (Nrf2 hyper-activation) bypasses KRIT1 to restore collagen transcription.","method":"RNAi knockdown of kri-1 in C. elegans, siRNA knockdown of KRIT1 and KEAP1 in human MRC-5 cells, collagen gene transcription assays, SKN-1/Nrf2 activation assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cross-species validation (C. elegans and human cells), epistasis placing KRIT1 upstream of Nrf2 in collagen regulation, two orthogonal systems, single lab","pmids":["33495402"],"is_preprint":false},{"year":2026,"finding":"C. elegans kri-1/KRIT1 restrains SKN-1/NRF2 transcription factor activity to control innate immune gene transcription and intestinal lipid mobilization during aging, but functions independently of skn-1/NRF2 to maintain intestinal epithelial barrier integrity and pathogen tolerance; kri-1 was identified in a forward genetic screen for innate immune gene transcription regulators.","method":"Forward genetic screen, loss-of-function genetic analysis, epistasis with skn-1, intestinal epithelial barrier integrity assay, immune gene transcription assays, lipid mobilization assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — forward genetic screen plus epistasis and multiple phenotypic readouts; preprint, not yet peer-reviewed","pmids":["42239296"],"is_preprint":true},{"year":2015,"finding":"In C. elegans excretory canal development, CCM-3 acts independently of the CCM1 orthologue KRI-1 for seamless tube extension; loss of kri-1 does not phenocopy loss of ccm-3 in canal morphology, establishing that KRI-1 and CCM-3 function in distinct branches of the CCM pathway.","method":"Loss-of-function genetic analysis, canal morphology imaging, genetic epistasis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with direct morphological readout distinguishing KRI-1 and CCM-3 functions, single lab","pmids":["25743393"],"is_preprint":false}],"current_model":"KRI1/Kri1 is a conserved nucleolar protein that physically interacts with Krr1 (via Krr1's KH1 domain) as part of the 90S pre-ribosome and is essential for early 18S rRNA processing and 40S ribosomal subunit biogenesis; in metazoans, the C. elegans ortholog KRI-1 (homolog of human KRIT1/CCM1) acts in intestinal cells as a scaffold that promotes DAF-16/FOXO nuclear localization downstream of lipophilic-hormone signaling from the germline, forms a complex with CCM-2 to negatively regulate ERK-5/MAPK and control zinc transporter expression for cell-nonautonomous regulation of germline apoptosis, and drives a redox-signaling module (H2S and ROS production) that activates SKN-1/NRF2 and the mitochondrial unfolded-protein response to extend lifespan, while also restraining excessive SKN-1/NRF2 activity to maintain innate immune and lipid homeostasis."},"narrative":{"mechanistic_narrative":"KRI1 encodes a conserved nucleolar protein with two distinct, evolutionarily separated functional identities documented in the corpus: a core role in ribosome biogenesis defined in yeast, and scaffold/signaling roles defined for the C. elegans ortholog KRI-1. In yeast, Kri1p localizes to the nucleolus and is essential for early 18S rRNA processing and 40S ribosomal subunit biogenesis, with its depletion abolishing 18S rRNA production while leaving 25S rRNA intact [PMID:11027267]. It is recruited to the 90S pre-ribosome through direct binding to Krr1, engaging the divergent, RNA-binding-deficient KH1 domain of Krr1 [PMID:24990943], and is delivered together with Krr1 and Utp23 to a snR30 snoRNP-chaperoned pre-18S rRNA platform subdomain whose integration depends on Krr1-mediated snR30 release [PMID:40399280]. In C. elegans, KRI-1 (homolog of human KRIT1/CCM1) acts cell-nonautonomously in the intestine as a signaling hub: it promotes DAF-16/FOXO nuclear localization downstream of germline lipophilic-hormone signaling to drive germline-loss lifespan extension [PMID:16530050], forms a complex with CCM-2 to negatively regulate ERK-5/MAPK and thereby permit KLF-3-driven zipt-2.3 zinc-transporter expression and IR-induced germline apoptosis [PMID:30996251, PMID:20137949], and generates H2S and ROS that activate SKN-1/Nrf2 and the mitochondrial unfolded-protein response [PMID:27140632]. KRI-1/KRIT1 sits upstream of SKN-1/Nrf2 in stress-induced collagen transcription, an arrangement conserved in human lung fibroblasts and bypassed by KEAP1 knockdown [PMID:33495402].","teleology":[{"year":2000,"claim":"Established Kri1p as a nucleolar factor physically partnered with Krr1p and functionally dedicated to the small-subunit branch of ribosome biogenesis, distinguishing it from large-subunit processing.","evidence":"Co-immunoprecipitation, nucleolar localization, polysome profiling and pulse-chase rRNA analysis with galactose-shutoff depletion in yeast","pmids":["11027267"],"confidence":"High","gaps":["Did not define the structural basis of the Kri1-Krr1 interaction","Did not place Kri1 within a defined pre-ribosomal assembly intermediate"]},{"year":2014,"claim":"Resolved how Kri1 is held in the pre-ribosome by showing the divergent KH1 domain of Krr1 — which lacks RNA-binding capacity — is the dedicated Kri1-docking surface, separating Krr1's protein-scaffolding and RNA-binding functions.","evidence":"Co-crystal structure at 2.8 Å with interaction-surface mutagenesis and 18S rRNA processing assays","pmids":["24990943"],"confidence":"High","gaps":["Did not directly map a Kri1 functional surface beyond the Krr1 interface","Functional consequence assayed was the Krr1-Faf1 interaction, not Kri1 directly"]},{"year":2025,"claim":"Placed Kri1 in the temporal order of 90S assembly, showing it is co-recruited with Krr1 and Utp23 to a snR30-chaperoned pre-18S platform subdomain whose incorporation requires Krr1-dependent snR30 release.","evidence":"Cryo-EM of 90S pre-ribosome intermediates with RNA hybridization blocking and recruitment assays in yeast","pmids":["40399280"],"confidence":"High","gaps":["Specific catalytic or chaperone activity contributed by Kri1 itself remains undefined","How Kri1 release or hand-off to later intermediates occurs is not resolved"]},{"year":2006,"claim":"Revealed an unexpected metazoan signaling role: the C. elegans ortholog acts in the intestine to drive DAF-16/FOXO nuclear localization specifically in the germline-loss longevity pathway, not the insulin/IGF-1 branch.","evidence":"Genetic epistasis, DAF-16::GFP nuclear localization imaging, lifespan assays with tissue-specific rescue in C. elegans","pmids":["16530050"],"confidence":"High","gaps":["Molecular mechanism by which KRI-1 promotes DAF-16 nuclear import is not defined","Relationship between the metazoan signaling role and the conserved nucleolar role is unaddressed"]},{"year":2010,"claim":"Showed KRI-1 controls germ cell apoptosis cell-nonautonomously from somatic cells and independently of cep-1/p53, defining an inter-tissue apoptotic signaling function.","evidence":"Loss-of-function genetics, cell-autonomous vs non-autonomous tissue-specific rescue, epistasis with cep-1, ced-4 and ced-3 in C. elegans","pmids":["20137949"],"confidence":"High","gaps":["The signal relayed from somatic cells to the germline was not molecularly identified","Direct biochemical partners mediating the non-autonomous signal were unknown at this stage"]},{"year":2013,"claim":"Identified DLC-1 as an upstream regulator that sets KRI-1 protein levels in the same IR-induced apoptosis pathway, providing a handle on KRI-1 abundance control.","evidence":"RNAi knockdown, genetic epistasis and KRI-1 protein level measurement in C. elegans germline apoptosis assays","pmids":["24030151"],"confidence":"Medium","gaps":["Mechanism by which DLC-1 controls KRI-1 protein levels (stability vs synthesis) not established","Limited mechanistic depth specifically for KRI-1"]},{"year":2016,"claim":"Connected KRI-1 to redox signaling by showing it generates H2S and ROS downstream of germline loss to activate SKN-1/Nrf2 and the mitochondrial UPR, linking the protein to longevity-associated stress responses.","evidence":"Genetic loss-of-function with tissue-resolved H2S and ROS measurement, mitochondrial biogenesis assays and epistasis with skn-1 in C. elegans","pmids":["27140632"],"confidence":"High","gaps":["Enzymatic source of KRI-1-dependent H2S/ROS not identified","Whether KRI-1 acts directly or via intermediate effectors in redox generation is unresolved"]},{"year":2019,"claim":"Defined a biochemical KRI-1/CCM-2 complex that suppresses ERK-5/MAPK to license KLF-3-driven zinc-transporter (zipt-2.3) expression, mechanistically linking KRI-1 to intestinal zinc sequestration and germline apoptosis.","evidence":"Reciprocal Co-IP, multi-gene genetic epistasis, zinc localization imaging in C. elegans and krit1-/- zebrafish, and germline apoptosis assays","pmids":["30996251"],"confidence":"High","gaps":["Structural basis of the KRI-1/CCM-2 interaction not determined","Direct molecular link between the complex and ERK-5 suppression not fully mapped"]},{"year":2021,"claim":"Placed KRI-1/KRIT1 upstream of SKN-1/Nrf2 in stress-induced collagen transcription and showed this ordering is conserved in human fibroblasts, with KEAP1 loss bypassing the requirement for KRIT1.","evidence":"RNAi in C. elegans and siRNA of KRIT1/KEAP1 in human MRC-5 cells with collagen transcription and Nrf2 activation assays","pmids":["33495402"],"confidence":"Medium","gaps":["Direct biochemical link between KRIT1 and the KEAP1-Nrf2 axis not established","Whether KRIT1 acts on KEAP1, Nrf2, or upstream redox inputs is not resolved"]},{"year":2026,"claim":"Extended the SKN-1/Nrf2 relationship to a restraining role, showing kri-1 limits Nrf2 activity to tune innate immune transcription and lipid mobilization while acting independently of skn-1 for epithelial barrier integrity.","evidence":"Forward genetic screen, epistasis with skn-1, intestinal barrier and immune/lipid assays in C. elegans (preprint)","pmids":["42239296"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Mechanism by which KRI-1 both activates and restrains SKN-1/Nrf2 in different contexts is not reconciled","skn-1-independent barrier function lacks a defined effector"]},{"year":null,"claim":"It remains unknown whether the conserved nucleolar ribosome-biogenesis function and the metazoan intestinal scaffold/signaling functions reflect a single biochemical activity deployed in different contexts or genuinely distinct roles of the same protein.","evidence":"No discovery in the corpus bridges the yeast nucleolar mechanism and the C. elegans signaling mechanisms","pmids":[],"confidence":"Low","gaps":["No structural or biochemical study connects KRI1's pre-ribosomal role to its FOXO/Nrf2/ERK signaling roles","Human KRI1 ribosome-biogenesis function not directly characterized in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1,2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4,5]}],"complexes":["90S pre-ribosome","KRI-1/CCM-2 complex"],"partners":["KRR1","CCM-2","DLC-1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N9T8","full_name":"Protein KRI1 homolog","aliases":[],"length_aa":703,"mass_kda":82.6,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8N9T8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/KRI1","classification":"Common Essential","n_dependent_lines":1065,"n_total_lines":1090,"dependency_fraction":0.9770642201834863},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NPM1","stoichiometry":0.2},{"gene":"RPS16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/KRI1","total_profiled":1310},"omim":[{"mim_id":"621355","title":"KRI1 HOMOLOG; KRI1","url":"https://www.omim.org/entry/621355"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/KRI1"},"hgnc":{"alias_symbol":["FLJ12949"],"prev_symbol":[]},"alphafold":{"accession":"Q8N9T8","domains":[{"cath_id":"-","chopping":"498-527","consensus_level":"medium","plddt":77.5893,"start":498,"end":527},{"cath_id":"-","chopping":"534-595","consensus_level":"high","plddt":85.8371,"start":534,"end":595},{"cath_id":"-","chopping":"662-696","consensus_level":"high","plddt":85.0686,"start":662,"end":696}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N9T8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N9T8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N9T8-F1-predicted_aligned_error_v6.png","plddt_mean":69.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KRI1","jax_strain_url":"https://www.jax.org/strain/search?query=KRI1"},"sequence":{"accession":"Q8N9T8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N9T8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N9T8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N9T8"}},"corpus_meta":[{"pmid":"16530050","id":"PMC_16530050","title":"Germ-cell loss extends C. elegans life span through regulation of DAF-16 by kri-1 and lipophilic-hormone signaling.","date":"2006","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/16530050","citation_count":275,"is_preprint":false},{"pmid":"27140632","id":"PMC_27140632","title":"Roles for ROS and hydrogen sulfide in the longevity response to germline loss in Caenorhabditis elegans.","date":"2016","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/27140632","citation_count":116,"is_preprint":false},{"pmid":"11027267","id":"PMC_11027267","title":"Yeast Krr1p physically and functionally interacts with a novel essential Kri1p, and both proteins are required for 40S ribosome biogenesis in the nucleolus.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11027267","citation_count":76,"is_preprint":false},{"pmid":"25743393","id":"PMC_25743393","title":"CCM-3/STRIPAK promotes seamless tube extension through endocytic recycling.","date":"2015","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25743393","citation_count":70,"is_preprint":false},{"pmid":"20137949","id":"PMC_20137949","title":"Cell-nonautonomous regulation of C. elegans germ cell death by kri-1.","date":"2010","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/20137949","citation_count":46,"is_preprint":false},{"pmid":"33397961","id":"PMC_33397961","title":"Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33397961","citation_count":33,"is_preprint":false},{"pmid":"23815345","id":"PMC_23815345","title":"The Caenorhabditis elegans LET-418/Mi2 plays a conserved role in lifespan regulation.","date":"2013","source":"Aging 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longevity.","date":"2010","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/20550516","citation_count":23,"is_preprint":false},{"pmid":"24990943","id":"PMC_24990943","title":"Interaction between ribosome assembly factors Krr1 and Faf1 is essential for formation of small ribosomal subunit in yeast.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24990943","citation_count":21,"is_preprint":false},{"pmid":"33745150","id":"PMC_33745150","title":"Genome-wide association study of stage III/IV grade C periodontitis (former aggressive periodontitis) in a Spanish population.","date":"2021","source":"Journal of clinical periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/33745150","citation_count":18,"is_preprint":false},{"pmid":"24030151","id":"PMC_24030151","title":"Cell-nonautonomous inhibition of radiation-induced apoptosis by dynein light chain 1 in Caenorhabditis elegans.","date":"2013","source":"Cell death & 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key regulator of collagen gene transcription.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33495402","citation_count":4,"is_preprint":false},{"pmid":"32524554","id":"PMC_32524554","title":"Generation and Analysis of CCM Phenotypes in C. elegans.","date":"2020","source":"Methods in molecular biology (Clifton, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/32524554","citation_count":2,"is_preprint":false},{"pmid":"41465363","id":"PMC_41465363","title":"Knockdown-Induced Fasting Phenotypes in Flatworms: Insights into Underlying Mechanisms of Feeding Behavior.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41465363","citation_count":1,"is_preprint":false},{"pmid":"42239296","id":"PMC_42239296","title":"kri-1/KRIT1 restrains skn-1/NRF2 activation to promote innate immune and lipid homeostasis.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42239296","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11033,"output_tokens":3272,"usd":0.04109,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10719,"output_tokens":3916,"usd":0.075747,"stage2_stop_reason":"end_turn"},"total_usd":0.116837,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"Yeast Kri1p physically interacts with Krr1p (co-immunoprecipitation of myc-tagged Kri1p with HA-tagged Krr1p), localizes to the nucleolus, and both proteins are required for 40S ribosome biogenesis; depletion of Kri1p abolishes 18S rRNA production while 25S rRNA levels remain normal.\",\n      \"method\": \"Co-immunoprecipitation, nucleolar localization by tagged protein, polysome profiling, pulse-chase rRNA analysis, Northern blot, galactose-shutoff depletion strain\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple orthogonal methods (localization, polysome profiling, pulse-chase, Northern), and genetic depletion with specific rRNA processing phenotype in a single rigorous study\",\n      \"pmids\": [\"11027267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of Krr1 shows it comprises two KH domains (KH1 and KH2); KH1 is a divergent domain lacking the RNA-binding GXXG motif and is the domain responsible for binding Kri1, while KH2 contains a canonical RNA-binding surface and binds Faf1. Disruption of the Krr1-Faf1 interaction (not directly Kri1) impairs early 18S rRNA processing at sites A0, A1, and A2.\",\n      \"method\": \"Co-crystal structure at 2.8 Å resolution, mutagenesis of interaction surfaces, 18S rRNA processing assays, cell lethality assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — co-crystal structure with functional mutagenesis and rRNA processing readout, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"24990943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In yeast 90S pre-ribosome assembly, Kri1 is recruited together with Krr1 and Utp23 to a pre-18S rRNA subdomain (platform helices and ES6) chaperoned by the snR30 snoRNP; Krr1-dependent release of snR30 is required for integration of the platform subdomain into the 90S pre-ribosome.\",\n      \"method\": \"Cryo-EM structural analysis of 90S pre-ribosome intermediates, RNA hybridization blocking experiments, assembly factor recruitment assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with functional validation of snR30 release and platform integration, single lab but multiple orthogonal structural and biochemical methods\",\n      \"pmids\": [\"40399280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"C. elegans kri-1 acts in the intestine to promote DAF-16/FOXO nuclear localization in response to lipophilic-hormone signaling from the germline; kri-1 is required for germ-cell-loss-induced lifespan extension but not for lifespan extension downstream of reduced insulin/IGF-1 signaling.\",\n      \"method\": \"Genetic epistasis, DAF-16::GFP nuclear localization imaging, lifespan assays in kri-1 mutants and tissue-specific rescue\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with direct subcellular localization readout, pathway placement established with tissue-specific rescue, replicated in multiple genetic backgrounds\",\n      \"pmids\": [\"16530050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"C. elegans kri-1 regulates DNA damage-induced germ cell apoptosis in a cell-nonautonomous manner, independently of cep-1/p53; kri-1 acts in nondying (somatic) cells to promote apoptosis in the germline.\",\n      \"method\": \"Loss-of-function genetics, tissue-specific rescue, epistasis with cep-1/p53 and core apoptosis pathway genes (ced-4, ced-3), germline apoptosis assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with cell-autonomous vs. non-autonomous rescue experiments and multiple pathway placements, single lab but multiple orthogonal genetic methods\",\n      \"pmids\": [\"20137949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C. elegans KRI-1 forms a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway, thereby allowing the KLF-3 transcription factor to drive expression of the SLC39 zinc transporter zipt-2.3, which sequesters zinc in the intestine; loss of KRI-1 reduces intestinal zinc sequestration and inhibits IR-induced MPK-1/ERK1 activation and germline apoptosis.\",\n      \"method\": \"Co-immunoprecipitation (KRI-1/CCM-2 complex), genetic epistasis (kri-1, ccm-2, klf-3, zipt-2.3), zinc localization imaging (in C. elegans and krit1-/- zebrafish), germline apoptosis assay, ERK pathway activation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex, multiple orthogonal genetic epistasis experiments, cross-species validation in zebrafish, and patient tissue data\",\n      \"pmids\": [\"30996251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"C. elegans KRI-1 plays a key role in generating H2S and reactive oxygen species (ROS) downstream of germline loss; kri-1-dependent H2S production activates SKN-1/Nrf2, and kri-1-dependent ROS activate the mitochondrial unfolded-protein response, both contributing to lifespan extension.\",\n      \"method\": \"Genetic loss-of-function, H2S and ROS measurement in specific tissues, mitochondrial biogenesis assays, epistasis with skn-1 and mitochondrial UPR pathway genes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical measurement of H2S and ROS combined with genetic epistasis and multiple orthogonal pathway readouts, single lab but strong evidence quality\",\n      \"pmids\": [\"27140632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"C. elegans DLC-1 (dynein light chain 1) functions cell-nonautonomously in the same pathway as kri-1 in response to ionizing radiation-induced apoptosis, and DLC-1 regulates the protein levels of KRI-1.\",\n      \"method\": \"RNAi knockdown, genetic epistasis, KRI-1 protein level measurement, germline apoptosis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic epistasis and protein level measurement, single lab, limited mechanistic depth for KRI-1 specifically\",\n      \"pmids\": [\"24030151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Inactivation of nhr-49/PPARα in C. elegans causes striking membrane localization of KRI-1, suggesting KRI-1 subcellular localization is regulated by NHR-49 and may operate in a positive feedback loop to potentiate DAF-16/FOXO and TCER-1 activity.\",\n      \"method\": \"KRI-1 subcellular localization imaging after nhr-49 RNAi, genetic interaction analysis\",\n      \"journal\": \"Worm\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization observation after RNAi, single lab, no functional rescue or mechanistic follow-up confirming the feedback loop\",\n      \"pmids\": [\"27073739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, KRI-1 is required for paraquat-induced activation of SKN-1/Nrf2 and consequent collagen gene transcription; in human lung fibroblasts (MRC-5), both KRIT1 and Nrf2 are required for collagen transcription in response to paraquat, and KEAP1 knockdown (Nrf2 hyper-activation) bypasses KRIT1 to restore collagen transcription.\",\n      \"method\": \"RNAi knockdown of kri-1 in C. elegans, siRNA knockdown of KRIT1 and KEAP1 in human MRC-5 cells, collagen gene transcription assays, SKN-1/Nrf2 activation assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cross-species validation (C. elegans and human cells), epistasis placing KRIT1 upstream of Nrf2 in collagen regulation, two orthogonal systems, single lab\",\n      \"pmids\": [\"33495402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"C. elegans kri-1/KRIT1 restrains SKN-1/NRF2 transcription factor activity to control innate immune gene transcription and intestinal lipid mobilization during aging, but functions independently of skn-1/NRF2 to maintain intestinal epithelial barrier integrity and pathogen tolerance; kri-1 was identified in a forward genetic screen for innate immune gene transcription regulators.\",\n      \"method\": \"Forward genetic screen, loss-of-function genetic analysis, epistasis with skn-1, intestinal epithelial barrier integrity assay, immune gene transcription assays, lipid mobilization assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — forward genetic screen plus epistasis and multiple phenotypic readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"42239296\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In C. elegans excretory canal development, CCM-3 acts independently of the CCM1 orthologue KRI-1 for seamless tube extension; loss of kri-1 does not phenocopy loss of ccm-3 in canal morphology, establishing that KRI-1 and CCM-3 function in distinct branches of the CCM pathway.\",\n      \"method\": \"Loss-of-function genetic analysis, canal morphology imaging, genetic epistasis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with direct morphological readout distinguishing KRI-1 and CCM-3 functions, single lab\",\n      \"pmids\": [\"25743393\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"KRI1/Kri1 is a conserved nucleolar protein that physically interacts with Krr1 (via Krr1's KH1 domain) as part of the 90S pre-ribosome and is essential for early 18S rRNA processing and 40S ribosomal subunit biogenesis; in metazoans, the C. elegans ortholog KRI-1 (homolog of human KRIT1/CCM1) acts in intestinal cells as a scaffold that promotes DAF-16/FOXO nuclear localization downstream of lipophilic-hormone signaling from the germline, forms a complex with CCM-2 to negatively regulate ERK-5/MAPK and control zinc transporter expression for cell-nonautonomous regulation of germline apoptosis, and drives a redox-signaling module (H2S and ROS production) that activates SKN-1/NRF2 and the mitochondrial unfolded-protein response to extend lifespan, while also restraining excessive SKN-1/NRF2 activity to maintain innate immune and lipid homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KRI1 encodes a conserved nucleolar protein with two distinct, evolutionarily separated functional identities documented in the corpus: a core role in ribosome biogenesis defined in yeast, and scaffold/signaling roles defined for the C. elegans ortholog KRI-1. In yeast, Kri1p localizes to the nucleolus and is essential for early 18S rRNA processing and 40S ribosomal subunit biogenesis, with its depletion abolishing 18S rRNA production while leaving 25S rRNA intact [#0]. It is recruited to the 90S pre-ribosome through direct binding to Krr1, engaging the divergent, RNA-binding-deficient KH1 domain of Krr1 [#1], and is delivered together with Krr1 and Utp23 to a snR30 snoRNP-chaperoned pre-18S rRNA platform subdomain whose integration depends on Krr1-mediated snR30 release [#2]. In C. elegans, KRI-1 (homolog of human KRIT1/CCM1) acts cell-nonautonomously in the intestine as a signaling hub: it promotes DAF-16/FOXO nuclear localization downstream of germline lipophilic-hormone signaling to drive germline-loss lifespan extension [#3], forms a complex with CCM-2 to negatively regulate ERK-5/MAPK and thereby permit KLF-3-driven zipt-2.3 zinc-transporter expression and IR-induced germline apoptosis [#5, #4], and generates H2S and ROS that activate SKN-1/Nrf2 and the mitochondrial unfolded-protein response [#6]. KRI-1/KRIT1 sits upstream of SKN-1/Nrf2 in stress-induced collagen transcription, an arrangement conserved in human lung fibroblasts and bypassed by KEAP1 knockdown [#9].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established Kri1p as a nucleolar factor physically partnered with Krr1p and functionally dedicated to the small-subunit branch of ribosome biogenesis, distinguishing it from large-subunit processing.\",\n      \"evidence\": \"Co-immunoprecipitation, nucleolar localization, polysome profiling and pulse-chase rRNA analysis with galactose-shutoff depletion in yeast\",\n      \"pmids\": [\"11027267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of the Kri1-Krr1 interaction\", \"Did not place Kri1 within a defined pre-ribosomal assembly intermediate\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how Kri1 is held in the pre-ribosome by showing the divergent KH1 domain of Krr1 — which lacks RNA-binding capacity — is the dedicated Kri1-docking surface, separating Krr1's protein-scaffolding and RNA-binding functions.\",\n      \"evidence\": \"Co-crystal structure at 2.8 Å with interaction-surface mutagenesis and 18S rRNA processing assays\",\n      \"pmids\": [\"24990943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not directly map a Kri1 functional surface beyond the Krr1 interface\", \"Functional consequence assayed was the Krr1-Faf1 interaction, not Kri1 directly\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed Kri1 in the temporal order of 90S assembly, showing it is co-recruited with Krr1 and Utp23 to a snR30-chaperoned pre-18S platform subdomain whose incorporation requires Krr1-dependent snR30 release.\",\n      \"evidence\": \"Cryo-EM of 90S pre-ribosome intermediates with RNA hybridization blocking and recruitment assays in yeast\",\n      \"pmids\": [\"40399280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific catalytic or chaperone activity contributed by Kri1 itself remains undefined\", \"How Kri1 release or hand-off to later intermediates occurs is not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed an unexpected metazoan signaling role: the C. elegans ortholog acts in the intestine to drive DAF-16/FOXO nuclear localization specifically in the germline-loss longevity pathway, not the insulin/IGF-1 branch.\",\n      \"evidence\": \"Genetic epistasis, DAF-16::GFP nuclear localization imaging, lifespan assays with tissue-specific rescue in C. elegans\",\n      \"pmids\": [\"16530050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which KRI-1 promotes DAF-16 nuclear import is not defined\", \"Relationship between the metazoan signaling role and the conserved nucleolar role is unaddressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed KRI-1 controls germ cell apoptosis cell-nonautonomously from somatic cells and independently of cep-1/p53, defining an inter-tissue apoptotic signaling function.\",\n      \"evidence\": \"Loss-of-function genetics, cell-autonomous vs non-autonomous tissue-specific rescue, epistasis with cep-1, ced-4 and ced-3 in C. elegans\",\n      \"pmids\": [\"20137949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The signal relayed from somatic cells to the germline was not molecularly identified\", \"Direct biochemical partners mediating the non-autonomous signal were unknown at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified DLC-1 as an upstream regulator that sets KRI-1 protein levels in the same IR-induced apoptosis pathway, providing a handle on KRI-1 abundance control.\",\n      \"evidence\": \"RNAi knockdown, genetic epistasis and KRI-1 protein level measurement in C. elegans germline apoptosis assays\",\n      \"pmids\": [\"24030151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which DLC-1 controls KRI-1 protein levels (stability vs synthesis) not established\", \"Limited mechanistic depth specifically for KRI-1\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected KRI-1 to redox signaling by showing it generates H2S and ROS downstream of germline loss to activate SKN-1/Nrf2 and the mitochondrial UPR, linking the protein to longevity-associated stress responses.\",\n      \"evidence\": \"Genetic loss-of-function with tissue-resolved H2S and ROS measurement, mitochondrial biogenesis assays and epistasis with skn-1 in C. elegans\",\n      \"pmids\": [\"27140632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic source of KRI-1-dependent H2S/ROS not identified\", \"Whether KRI-1 acts directly or via intermediate effectors in redox generation is unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a biochemical KRI-1/CCM-2 complex that suppresses ERK-5/MAPK to license KLF-3-driven zinc-transporter (zipt-2.3) expression, mechanistically linking KRI-1 to intestinal zinc sequestration and germline apoptosis.\",\n      \"evidence\": \"Reciprocal Co-IP, multi-gene genetic epistasis, zinc localization imaging in C. elegans and krit1-/- zebrafish, and germline apoptosis assays\",\n      \"pmids\": [\"30996251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the KRI-1/CCM-2 interaction not determined\", \"Direct molecular link between the complex and ERK-5 suppression not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed KRI-1/KRIT1 upstream of SKN-1/Nrf2 in stress-induced collagen transcription and showed this ordering is conserved in human fibroblasts, with KEAP1 loss bypassing the requirement for KRIT1.\",\n      \"evidence\": \"RNAi in C. elegans and siRNA of KRIT1/KEAP1 in human MRC-5 cells with collagen transcription and Nrf2 activation assays\",\n      \"pmids\": [\"33495402\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between KRIT1 and the KEAP1-Nrf2 axis not established\", \"Whether KRIT1 acts on KEAP1, Nrf2, or upstream redox inputs is not resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended the SKN-1/Nrf2 relationship to a restraining role, showing kri-1 limits Nrf2 activity to tune innate immune transcription and lipid mobilization while acting independently of skn-1 for epithelial barrier integrity.\",\n      \"evidence\": \"Forward genetic screen, epistasis with skn-1, intestinal barrier and immune/lipid assays in C. elegans (preprint)\",\n      \"pmids\": [\"42239296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Mechanism by which KRI-1 both activates and restrains SKN-1/Nrf2 in different contexts is not reconciled\", \"skn-1-independent barrier function lacks a defined effector\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether the conserved nucleolar ribosome-biogenesis function and the metazoan intestinal scaffold/signaling functions reflect a single biochemical activity deployed in different contexts or genuinely distinct roles of the same protein.\",\n      \"evidence\": \"No discovery in the corpus bridges the yeast nucleolar mechanism and the C. elegans signaling mechanisms\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical study connects KRI1's pre-ribosomal role to its FOXO/Nrf2/ERK signaling roles\", \"Human KRI1 ribosome-biogenesis function not directly characterized in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"90S pre-ribosome\", \"KRI-1/CCM-2 complex\"],\n    \"partners\": [\"KRR1\", \"CCM-2\", \"DLC-1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}