KRI1

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).

1. 2000 High

   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

   PMID:11027267

   Open questions at the time

   • Did not define the structural basis of the Kri1-Krr1 interaction
   • Did not place Kri1 within a defined pre-ribosomal assembly intermediate
2. 2014 High

   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

   PMID:24990943

   Open questions at the time

   • Did not directly map a Kri1 functional surface beyond the Krr1 interface
   • Functional consequence assayed was the Krr1-Faf1 interaction, not Kri1 directly
3. 2025 High

   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

   PMID:40399280

   Open questions at the time

   • Specific catalytic or chaperone activity contributed by Kri1 itself remains undefined
   • How Kri1 release or hand-off to later intermediates occurs is not resolved
4. 2006 High

   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

   PMID:16530050

   Open questions at the time

   • 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
5. 2010 High

   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

   PMID:20137949

   Open questions at the time

   • 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
6. 2013 Medium

   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

   PMID:24030151

   Open questions at the time

   • Mechanism by which DLC-1 controls KRI-1 protein levels (stability vs synthesis) not established
   • Limited mechanistic depth specifically for KRI-1
7. 2016 High

   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

   PMID:27140632

   Open questions at the time

   • Enzymatic source of KRI-1-dependent H2S/ROS not identified
   • Whether KRI-1 acts directly or via intermediate effectors in redox generation is unresolved
8. 2019 High

   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

   PMID:30996251

   Open questions at the time

   • Structural basis of the KRI-1/CCM-2 interaction not determined
   • Direct molecular link between the complex and ERK-5 suppression not fully mapped
9. 2021 Medium

   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

   PMID:33495402

   Open questions at the time

   • 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
10. 2026 Medium

    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)

    PMID:42239296

    Open questions at the time

    • 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

• 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.
• 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