Extracellular matrices (ECMs) mechanically support tissues of multicellular organisms. Barrier ECMs at the surface of animals act as a first line defense to many environmental stressors. ECM regulation of stress responsive gene expression remains poorly understood in animals but has the potential to influence development, aging, and clinically relevant conditions such as tissue fibrosis and tumorigenesis. We and others identified annular furrows in C. elegans, repeating circumferential bands of collagen in the cuticle, as an ECM structure required for regulation of stress responses. Genetic disruption of furrow collagen genes (
dpy-2, 3, 7, 8, 9, and 10) induces organic osmolyte, detoxification, and antimicrobial genes in the absence of environmental stress. Mutation or loss of four non-collagen proteins secreted from epidermal cells (OSR-1, OSM-7, OSM-8, and OSM-11) activates the same stress responses without obvious changes to the cuticle indicating that other extracellular proteins are involved. To identify downstream signaling mechanisms, we conducted an RNAi screen of protein kinases in
dpy-7 worms. Loss of
drl-1, Dietary Restriction-Like kinase, suppresses stress response gene expression and acute osmotic stress resistance in
dpy-7 and
dpy-10 worms. Loss of
drl-1 also suppresses the same phenotypes in
osm-7 and
osm-8 worms. Alternatively, loss of
drl-1 does not reduce stress response gene expression under basal conditions or during oxidative stress consistent with specificity to extracellular signals. DRL-1 has a kinase domain homologous to mammalian MEKK-3, which has been implicated in regulation of cell osmotic responses via
p38 MAPK. RNAi of
drl-1 was previously shown to increase fat metabolism and extend lifespan in C. elegans by a mechanism similar to dietary restriction. Genetic interaction analyses suggest that dietary restriction and
p38 MAPK have no effect or function parallel to DRL-1, respectively. Therefore, DRL-1 likely regulates stress responses downstream from the extracellular signals via a distinct mechanism. This work was supported by National Science Foundation grant IOS-1452948.