Systemic and cell intrinsic roles of Gqα signaling in the regulation of innate immunity, oxidative stress, and longevity in Caenorhabditis elegans

Signal transduction pathways that regulate longevity, immunity, and stress resistance can profoundly affect organismal survival. We show that a signaling module formed by the G protein alpha subunit, Gqα, and one of its downstream signal transducer phospholipase C β (PLCβ) can differentially affect these processes. Loss of Gqα and PLCβ functions result in increased sensitivity to pathogens and oxidative stress but confer life span extension. Gqα and PLCβ modulate life span and immunity noncell autonomously by affecting the activity of insulin/IGF1 signaling (IIS). In addition, Gqα and PLCβ function cell autonomously within the intestine to affect the activity of the p38 MAPK pathway, an important component of Caenorhabditis elegans immune and oxidative stress response. p38 MAPK activity in the intestine is regulated by diacylglycerol levels, a product of PLCβ's hydrolytic activity. We provide genetic evidence that life span is largely determined by IIS, whereas p38 MAPK signaling is the primary regulator of oxidative stress in PLCβ mutants. Pathogen sensitivity of Gqα and PLCβ mutants is a summation of the beneficial effects of decreased IIS through reduced neuronal secretion and the detrimental effects of reduced activity of intestinal p38 MAPK. We propose a model whereby Gqα signaling differentially regulates pathogen sensitivity, oxidative stress, and longevity through cell autonomous and noncell autonomous effects on p38 MAPK and insulin/IGF1 signaling, respectively.