Max Perutz Lecture 2014: C. elegans surveillance of conserved cellular components to detect and defend pathogen attacks, real or imagined

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• Gary Ruvkun, MGH Harvard
• Friday 05 December 2014, 16:15-18:00
• Max Perutz Lecture Theatre, Medical Research Council (MRC) (MRC Laboratory of Molecular Biol.

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RNAi-based gene inactivations targeting the core cellular components induce C. elegans to avoid the lawn of bacteria expressing those gene inactivating dsRNAs. Many of these gene inactivations that cause aversive behaviors encode the most conserved proteins of eukaryotes, from the ribosome, mitochondria, cytoskeleton, and proteasome. And many are targets of antibiotics produced by fungi and microbes. Toxins that target the same proteins also cause these aversive behaviors. C. elegans pathogen response and detoxification cytochrome p450 genes are also induced by E. coli expressing aversive C. elegans dsRNAs or drugs. Thus C. elegans interprets the E. coli that express just a single dsRNA that targets a C. elegans gene encoding a ribosomal protein for example as a pathogenic bacteria. A key prediction of this xenobiotic and bacterial virulence factor surveillance model is that even a chromosomal mutation disrupting for example a surveilled ribosomal component will cause induction of detoxification and pathogen responses. As predicted, various mutations that cause translation defects only in the germline induce the expression of particular cytochrome and ABC transporter genes in the intestine. In a functional genomic screen for animals that now fail to express these detoxification responses to these germline translation defects, that animals that are now “blind” to their translation defects, we found a kinase signaling cascade to p38 MAPK and to the ZIP -2/bZip and SKN -1/Nrf2 transcription factors and upstream steps in a lipid biosynthetic pathway. Mammalian bile acids can rescue the defect in detoxification gene induction caused by these C. elegans lipid biosynthetic gene inactivations. Similarly, crude hydrophobic extracts prepared from C. elegans with translation deficits but not extracts from wild type can rescue detoxification gene induction. These bile acids are likely to be a hormonal signal of translational malaise between the germline and the somatic intestine. Germline translation defects induce p38 MAPK phosphorylation and nuclear localization in the intestine and particular kinase and lipid biosynthetic genes that emerged from the RNAi screen act upstream of this, ordering the pathway components identified. These eukaryotic antibacterial countermeasures are not ignored by bacteria: we identified 3 bacterial species that actively suppress C. elegans detoxification responses to ribosomal mutations. This screen identifies genetic components of the core cellular component surveillance systems, the endocrine systems of spreading the detoxification signal systemically, and the coupling of these signals to upregulation of xenobiotic detoxification and anti-bacterial pathogenesis systems. Human variation in the homologues of these genes may underlie aberrant upregulation of drug detoxification and innate immunity pathways in the absence of a toxic or pathogen, for example, autoimmunity or feeding dysfunctions. The endocrine state of our aversively stimulated C. elegans may be homologous to the endocrine state of humans who feel unwell. The genetic suppressors of this aversive behavior we have identified may reveal an endocrinology of feeling ill or well.

This talk is part of the MRC LMB Seminar Series series.

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