Biology subjects

Peterson, N. D.

Publications and source records attributed to Peterson, N. D..

5 recordsLinked to original sources

bioRxiv2026

kri-1/KRIT1 restrains skn-1/NRF2 activation to promote innate immune and lipid homeostasis

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 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.

genetics↗

bioRxiv2023

Pathogen effector-triggered aggregation of TIR-1/SARM1 on lysosome-related organelles activates intestinal immunity

TIR-domain proteins with enzymatic activity are essential for immunity in plants, animals, and bacteria. However, it is not known how these proteins function in pathogen sensing in animals. We discovered that a TIR-domain protein (TIR-1/SARM1) is strategically expressed on the membranes of a lysosomal sub-compartment, which enables intestinal epithelial cells in the nematode C. elegans to survey for pathogen effector-triggered host damage. We showed that a redox active virulence effector secreted by the bacterial pathogen Pseudomonas aeruginosa alkalinized and condensed a specific subset of lysosomes by inducing intracellular oxidative stress. Concentration of TIR-1/SARM1 on the surface of these organelles triggered its multimerization, which engages its intrinsic NADase activity, to activate the p38 innate immune pathway and protect the host against microbial intoxication. Thus, lysosomal TIR-1/SARM1 is a sensor for oxidative stress induced by pathogenic bacteria to activate metazoan intestinal immunity.

immunology↗

bioRxiv2023

Transcriptional suppression of sphingolipid catabolism controls pathogen resistance in C. elegans

Sphingolipids are required for diverse biological functions and are degraded by specific catabolic enzymes. However, the mechanisms that regulate sphingolipid catabolism are not known. Here we characterize a transcriptional axis that regulates sphingolipid breakdown to control resistance against bacterial infection. From an RNAi screen for transcriptional regulators of pathogen resistance in the nematode C. elegans, we identified the nuclear hormone receptor nhr-66, a ligand-gated transcription factor homologous to human hepatocyte nuclear factor 4. Tandem chromatin immunoprecipitation-sequencing and RNA sequencing experiments revealed that NHR-66 is a transcriptional repressor, which directly targets sphingolipid catabolism genes. Transcriptional de-repression of two sphingolipid catabolic enzymes in nhr-66 loss-of-function mutants drives the breakdown of sphingolipids, which enhances host susceptibility to infection with the bacterial pathogen Pseudomonas aeruginosa. These data define transcriptional control of sphingolipid catabolism in the regulation of cellular sphingolipids, a process that is necessary for pathogen resistance.

immunology↗

bioRxiv2022

Bacterial pattern recognition in C. elegans by a nuclear hormone receptor

Pattern recognition of bacterial products by host receptors is essential for innate immunity in many metazoans. Curiously, the nematode lineage lost canonical mechanisms of bacterial pattern recognition. Whether other immune receptors evolved in their place is not known. Here, we characterize the first bacterial pattern recognition receptor and its natural ligand in the nematode Caenorhabditis elegans. We show that the C. elegans nuclear hormone receptor NHR-86/HNF4 senses phenazine-1-carboxamide (PCN), a metabolite produced by pathogenic strains of Pseudomonas aeruginosa. PCN binds to the ligand-binding domain of NHR-86/HNF4, a ligand-gated transcription factor, and activates an anti-pathogen transcriptional program in intestinal epithelial cells that provides protection against P. aeruginosa. These data de-orphan a nuclear hormone receptor and demonstrate that surveillance of metabolite signals from bacteria allows nematodes to identify virulent pathogens in their environment that are poised to cause disease.

immunology↗

bioRxiv2021

Sterol scarcity primes p38 immune defenses through a TIR-1/SARM1 phase transition

Intracellular signaling regulators can be concentrated into membrane-free, higher-ordered protein assemblies to initiate protective responses during stress -- a process known as phase transition. Here, we show that a phase transition of the Caenorhabditis elegans Toll/interleukin-1 receptor domain protein (TIR-1), an NAD+ glycohydrolase homologous to mammalian sterile alpha and TIR motif-containing 1 (SARM1), underlies p38 PMK-1 immune pathway activation in C. elegans intestinal epithelial cells. Through visualization of fluorescently labeled TIR-1/SARM1 protein, we demonstrate for the first time that physiologic stresses, both pathogen and non-pathogen, induce multimerization of TIR-1/SARM1 into visible puncta within intestinal epithelial cells. In vitro enzyme kinetic analyses revealed that, like mammalian SARM1, the NAD+ glycohydrolase activity of C. elegans TIR-1 is dramatically potentiated by protein oligomerization and a phase transition. Accordingly, C. elegans with genetic mutations that specifically block either multimerization or the NAD+ glycohydrolase activity of TIR-1/SARM1 fail to induce p38 PMK phosphorylation, are unable to increase immune effector expression, and are dramatically susceptible to bacterial infection. Finally, we demonstrate that the TIR-1/SARM1 phase transition is modified by dietary cholesterol, revealing a new adaptive response that allows a metazoan host to anticipate pathogen threats during micronutrient deprivation, a time of relative susceptibility to infection. When cholesterol is limited, TIR-1/SARM1 oligomerizes into puncta in intestinal epithelial cells and engages its NAD+ glycohydrolase activity, which increases p38 PMK-1 phosphorylation, and primes immune effector induction in a manner that promotes pathogen clearance from the intestine during a subsequent infection. Thus, a phase transition of TIR-1/SARM1 as a prerequisite for its NAD+ glycohydrolase activity is strongly conserved across millions of years of evolution and is essential for diverse physiological processes in multiple cell types.

immunology↗