Abstract
The tumor suppressor p53 has been implicated in multiple functions that play key roles in health and disease, including ribosome biogenesis, control of aging, and cell cycle regulation. A genetic screen for negative regulators of innate immunity in Caenorhabditis elegans led to the identification of a mutation in NOL-6, a nucleolar RNA-associated protein (NRAP), which is involved in ribosome biogenesis and conserved across eukaryotic organisms. Mutation or silencing of NOL-6 and other nucleolar proteins results in an enhanced resistance to bacterial infections. A full-genome microarray analysis on animals with altered immune function due to mutation in nol-6 shows increased transcriptional levels of genes regulated by a p53 homologue, CEP-1. Further studies indicate that the activation of innate immunity by inhibition of nucleolar proteins requires p53/CEP-1 and its transcriptional target SYM-1. Since nucleoli and p53/CEP-1 are conserved, our results reveal an ancient immune mechanism by which the nucleolus may regulate immune responses against bacterial pathogens.
Highlights
The relatively simple innate immune system of the nematode Caenorhabditis elegans and the number of traits that facilitate genetic and genomic analysis using this organism have led to the discovery of several pathways that regulate innate immune responses to pathogen infections
We provide evidence indicating that nucleolar proteins suppress innate immunity against bacteria by preventing the transcriptional activity of p53
Animals lacking NOL-6 and other nucleolar proteins were found to be resistant to infections by bacterial pathogens
Summary
The relatively simple innate immune system of the nematode Caenorhabditis elegans and the number of traits that facilitate genetic and genomic analysis using this organism have led to the discovery of several pathways that regulate innate immune responses to pathogen infections. Many of the C. elegans innate immune pathways integrate responses to pathogens, oxygen, and various stresses [1,2,3,4] This suggests that multiple stress-sensing mechanisms are activated in response to bacterial infection. In addition to binding to the transactivation domain of p53 [9,10], MDM2 functions as an E3 ubiquitin ligase which targets p53 for export to the cytoplasm and/or proteasome-mediated degradation [11,12,13]. This auto-regulatory feedback loop likely acts to restrain p53 function in normal cells, in the absence of stress. The Skp1/cullin/F-box (SCF) E3 ubiquitin ligase FSN-1 appears to negatively regulate endogenous CEP-1 protein phosphorylation levels [22]
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