Conserved nutrient sensor O-GlcNAc transferase is integral to C. elegans pathogen-specific immunity.

Michelle R Bond,Salil K Ghosh,John A Hanover,Peng Wang,Robin Charles May

doi:10.1371/journal.pone.0113231

Abstract

Discriminating pathogenic bacteria from bacteria used as a food source is key to Caenorhabidits elegans immunity. Using mutants defective in the enzymes of O-linked N-acetylglucosamine (O-GlcNAc) cycling, we examined the role of this nutrient-sensing pathway in the C. elegans innate immune response. Genetic analysis showed that deletion of O-GlcNAc transferase (ogt-1) yielded animals hypersensitive to the human pathogen S. aureus but not to P. aeruginosa. Genetic interaction studies revealed that nutrient-responsive OGT-1 acts through the conserved β-catenin (BAR-1) pathway and in concert with p38 MAPK (PMK-1) to modulate the immune response to S. aureus. Moreover, whole genome transcriptional profiling revealed that O-GlcNAc cycling mutants exhibited deregulation of unique stress- and immune-responsive genes. The participation of nutrient sensor OGT-1 in an immunity module evolutionarily conserved from C. elegans to humans reveals an unexplored nexus between nutrient availability and a pathogen-specific immune response.

Highlights

Immunity and metabolism are inextricably linked, evolutionarily conserved systems required for the appropriate distinction between nutrient and pathogen
We previously demonstrated genetic interactions between O-GlcNAc cycling and insulin signaling in C. elegans [16] and we sought to determine if interactions exist between O-GlcNAc cycling and the MAPK and b-catenin pathways
We found that the median survival values for double mutant ogt-1; pmk-1 and oga-1; pmk-1 animals exposed to P. aeruginosa had longevities that were indistinguishable from pmk-1 single mutants (Figure 2A–D, Table S1) suggesting neither OGT-1 nor OGA-1 are involved in the C. elegans innate immune response to P. aeruginosa

Summary

Introduction

Immunity and metabolism are inextricably linked, evolutionarily conserved systems required for the appropriate distinction between nutrient and pathogen. O-GlcNAc Transferase Impacts C. elegans Immunity between bacteria as a nutrient or pathogen is critical as bacteria in decaying organic matter is an essential component of their diet In this manuscript, we outline data that identify that the evolutionarily conserved, nutrient responsive enzyme O-GlcNAc transferase (OGT-1) is required for C. elegans to mount an appropriate innate immune response against select pathogens. 2–5% of glucose is converted to UDP-GlcNAc, which is, in part, used to posttranslationally modify serine and threonine residues with O-linked Nacetylglucosamine (O-GlcNAc) This posttranslational modification (PTM) plays a role in a variety of cellular processes ranging from protein folding and enzyme activity to cell signaling (for review, see Zachara et al and references therein) [3]. It has been shown that mammalian OGT interacts genetically and physically with evolutionarily conserved proteins known to play key roles in the immune response, including b-catenin [6,7,8,9] and p38 MAPK [10]

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