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

Abstract

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.insulin/IGF-1 signaling | p38 MAPK signaling | infection | aging A ppropriate responses to endogenous and exogenous threats at the organismal level are achieved by the coordination and integration of both cell-intrinsic and systemic signaling events. The conserved insulin/IGF1 signaling (IIS) pathway regulates life span, stress responses, and immunity. In Caenorhabditis elegans, activation of the insulin/IGF1-like receptor (IGFR) DAF-2 results in phosphorylation and retention of the forkhead transcription factor DAF-16 in the cytoplasm (1). Reduction in IGFR function results in increased life span and oxidative stress resistance in C. elegans (2, 3), Drosophila (4), and mice (5). Oxidative stress response is also regulated by the p38 MAPK cascade, which in C. elegans comprises of a three-tiered kinase cascade leading to phosphorylation by a MAPK kinase homolog SEK-1 and activation of the p38 MAPK homolog PMK-1 (6). Loss of either sek-1 or pmk-1 function results in increased sensitivity to oxidative stress (7). The p38 MAPK pathway affects oxidative stress resistance cell autonomously in part through regulation of the Nrf family transcription factor SKN-1 in the intestine (8, 9).IIS and p38 MAPK signaling contribute to C. elegans immunity. Diminished IIS confers pathogen resistance because of derepression of DAF-16 transcriptional activity and increased immuneeffector gene expression (10, 11), whereas diminished p38 MAPK signaling confers increased pathogen sensitivity (12); these pathways regulate distinct sets of immune-related genes (13-15). Re...

An Evolutionarily Conserved PLC-PKD-TFEB Pathway for Host Defense

“…PLC can be activated by interaction with α subunits of heterotrimeric Gq proteins, or Gα q (Taylor et al, 1991). Furthermore, previous work showed that the C. elegans Gα q homolog EGL-30 can activate PLCβ homolog EGL-8 for host defense against Pseudomonas aeruginosa or Microbacterium nematophilum infection (Kawli et al, 2010; McMullan et al, 2012). In addition, activation of EGL-30 during fungal infection triggers EGL-8 and Ca 2+ release to activate dual oxidase, or Duox (Zou et al, 2013).…”

“…In such pathway, a GPCR-Gα 12 -PLCγ-PKCδ pathway controls a STAT-type transcription factor (Dierking et al, 2011; Ziegler et al, 2009; Zugasti et al, 2014). C. elegans Gα q also has known roles upstream of PLCβ for the regulation of host defense against P. aeruginosa and oxidative stress (Kawli et al, 2010) and for the upregulation of transcription factor DAF-16 in the epidermis during D. coniospora infection (Zou et al, 2013). Furthermore, C. elegans Gα q was recently shown to control both innate immunity and infection avoidance behavior against M. nematophilum (McMullan et al, 2012).…”

Autophagy protects C. elegans against necrosis during Pseudomonas aeruginosa infection

“…The innate immunity in C. elegans is triggered by several signaling cascades, including PMK-1, DAF-16, MPK-1, DKF-2, FSHR-1, and EGL-30 (14,(16)(17)(18)(19)(20)(21). The active role of autophagy in innate immune responses to P. aeruginosa PA14 in C. elegans led us to hypothesize that one of these signaling pathways could mediate autophagy.…”

“…So far, the following major signaling cascades have been identified as involved in C. elegans defense against pathogenic bacteria: the p38 mitogen-activated protein kinase (MAPK) PMK-1 (16), , the extracellular signal-regulated kinase (ERK) MAPK MPK-1 (14,18), the protein kinase D DKF-2 (19), the G protein-coupled receptor FSHR-1 (20), and the G protein Gqα EGL-30 (21). Here, we investigated the function of autophagy in innate immune responses to P. aeruginosa PA14 in C. elegans.…”

The Role of Reactive Oxygen Species in Modulating the Caenorhabditis elegans Immune Response

“…Initial studies did not observe a role for the C . elegans major oxidative stress response transcription factor SKN-1 during infection [34,35], but further work, with additional controls, carried out by two independent laboratories discovered SKN-1 to be protective [32,33]. During infection, SKN-1 activation increases the expression of antioxidants in a BLI-3-dependent manner enhancing survival.…”