Orchestrating responses to environmental perturbations of homeostasis relies on the action of various signal transduction pathways, with mitogen-activated protein kinase (MAPK) pathways being prominent representatives. Three main MAPK pathways, the
p38, JNK and ERK, employ kinase activation cascades to induce protective responses during infection, wounding, oxidative stress and heavy metal exposure, to name a few. The consequences of MAPK pathway activation in response to various conditions are context-dependent. Age is one such context, but is rarely considered when studying these signaling pathways. Here we describe a switch occurring in C. elegans between the fourth larval stage (L4) and the two-day-old adult, in which the effect of MAPK activation changes from being protective to detrimental. The switch is manifested following the knockdown of
vhp-1 expression.
vhp-1 encodes a phosphatase that dephosphorylates and deactivates both the
p38 MAPK homolog PMK-1 and the JNK-like MAPK KGB-1 [1, 2]. Exposing worms from the egg stage until L4 to RNAi directed against
vhp-1 resulted in increased resistance to infection with Pseudomonas aeruginosa. However, worms exposed for the same duration to
vhp-1 RNAi beginning at the L4 stage, or for a twice-as-long duration starting at the egg stage, became more sensitive to the pathogen and showed a significant shortening of their general lifespan when grown on dead E. coli. Genetic analyses supplemented with Western blots to follow MAPK phosphorylation showed that both pathways are activated in either age. However, whereas pathogen resistance following
vhp-1 knock-down at the young age is dependent on
pmk-1 alone, increased pathogen susceptibility and the shortening of lifespan two days later is dependent solely on
kgb-1. Our results demonstrate a shift in dominance between two MAPK pathways, where beneficial effects surmount detrimental ones early in life, but this balance overturns later in life. 1. Mizuno, T., et al., EMBO J 2004. 23: 2226-2234. 2. Kim, D. H., et al., Proc Natl Acad Sci U S A 2004. 101: 10990-10994.