kri-1/KRIT1 promotes innate immune and lipid homeostasis in the C. elegans intestine
- 1Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, Massachusetts, United States of America
Abstract
Animals must differentially allocate essential metabolic resources in response to changing environmental conditions to ensure reproductive success. For example, adult C. elegans coordinate innate immune defenses during infection and also allocate fat stores to the germline, each of which are required for evolutionary fitness. The genetic mechanisms that integrate resource allocation and host defenses in this context, however, are not fully understood. From a forward genetic screen for novel regulators of innate immune gene transcription, we identified kri-1, the nematode homolog of human Krev interaction trapped protein KRIT1. Mutations in human KRIT1 underlie cerebral cavernous malformations, a disease marked by defects in vascular integrity. Similarly, C. elegans kri-1/KRIT1 is required for the integrity of the intestinal epithelial cell barrier. We find also that kri-1/KRIT1 is required for host tolerance to bacterial infection, fecundity, and normal development. In this context, kri-1/KRIT1 restrains the activity of the cytoprotective transcription factor skn-1/NRF2 to control immune gene transcription and likely intestinal lipid mobilization during aging, a process necessary for healthy reproduction, but functions independently of skn-1/NRF2 to promote epithelial integrity and pathogen tolerance. These data reveal a broad role for a strongly conserved regulator in essential physiological processes that are required for reproductive fidelity and evolutionary success. Author summary: To survive and reproduce, animals must defend against biotic and abiotic threats, and also allocate metabolic resources to the germline at the appropriate time to support reproductive fidelity. Here we discover that the conserved gene kri-1/KRIT ensures evolutionarily fitness of C. elegans by promoting resistance to bacterial infection, ensuring the integrity of the intestinal epithelial barrier, and controlling the mobilization of lipids from the soma to the germline to support reproduction. Thus, a single regulator that is strongly conserved across the animal branch of the tree of life is a lynchpin coordinator of essential host responses, which are required for reproductive, and thus evolutionary, success of an individual animal.
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BibTeX
@article{alaghatta2026kri1krit1,
title = {{kri-1/KRIT1 promotes innate immune and lipid homeostasis in the C. elegans intestine}},
author = {Akshay Alaghatta and Samantha Y. Tse-Kang and Daniel Bollen and Khursheed A. Wani and Nicholas D. Peterson and Read Pukkila-Worley},
journal = {PLOS Genetics},
year = {2026},
month = oct,
doi = {10.1371/journal.pgen.1012166},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012166},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - kri-1/KRIT1 promotes innate immune and lipid homeostasis in the C. elegans intestine
AU - Akshay Alaghatta
AU - Samantha Y. Tse-Kang
AU - Daniel Bollen
AU - Khursheed A. Wani
AU - Nicholas D. Peterson
AU - Read Pukkila-Worley
PY - 2026
DA - 2026/10/30
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012166
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012166
AB - Animals must differentially allocate essential metabolic resources in response to changing environmental conditions to ensure reproductive success. For example, adult C. elegans coordinate innate immune defenses during infection and also allocate fat stores to the germline, each of which are required for evolutionary fitness. The genetic mechanisms that integrate resource allocation and host defenses in this context, however, are not fully understood. From a forward genetic screen for novel regulators of innate immune gene transcription, we identified kri-1, the nematode homolog of human Krev interaction trapped protein KRIT1. Mutations in human KRIT1 underlie cerebral cavernous malformations, a disease marked by defects in vascular integrity. Similarly, C. elegans kri-1/KRIT1 is required for the integrity of the intestinal epithelial cell barrier. We find also that kri-1/KRIT1 is required for host tolerance to bacterial infection, fecundity, and normal development. In this context, kri-1/KRIT1 restrains the activity of the cytoprotective transcription factor skn-1/NRF2 to control immune gene transcription and likely intestinal lipid mobilization during aging, a process necessary for healthy reproduction, but functions independently of skn-1/NRF2 to promote epithelial integrity and pathogen tolerance. These data reveal a broad role for a strongly conserved regulator in essential physiological processes that are required for reproductive fidelity and evolutionary success. Author summary: To survive and reproduce, animals must defend against biotic and abiotic threats, and also allocate metabolic resources to the germline at the appropriate time to support reproductive fidelity. Here we discover that the conserved gene kri-1/KRIT ensures evolutionarily fitness of C. elegans by promoting resistance to bacterial infection, ensuring the integrity of the intestinal epithelial barrier, and controlling the mobilization of lipids from the soma to the germline to support reproduction. Thus, a single regulator that is strongly conserved across the animal branch of the tree of life is a lynchpin coordinator of essential host responses, which are required for reproductive, and thus evolutionary, success of an individual animal.
SN - 1553-7404
ER -