Loss of FIC-1-mediated AMPylation activates the UPR and upregulates cytosolic HSP70 chaperones to suppress polyglutamine toxicity.

Targeted regulation of cellular proteostasis machinery represents a promising strategy for the attenuation of pathological protein aggregation. Recent work suggests that the unfolded protein response in the endoplasmic reticulum (UPR ) directly regulates the aggregation and toxicity of expanded polyglutamine (polyQ) proteins. However, the mechanisms underlying this phenomenon remain poorly understood. In this study, we report that perturbing ER homeostasis in through the depletion of either BiP ortholog, or causes developmental arrest in worms expressing aggregation-prone polyQ proteins. This phenotype is rescued by the genetic deletion of the conserved UPR regulator, FIC-1. We demonstrate that the beneficial effects of knock-out (KO) extend into adulthood, where the loss of FIC-1-mediated protein AMPylation in polyQ-expressing animals is sufficient to prevent declines in fitness and lifespan. We further show that loss of and leads to distinct, but complementary transcriptomic responses to ER stress involving all three UPR stress sensors (IRE-1, PEK-1, and ATF-6). We identify the cytosolic HSP70 family chaperone , whose expression is increased in -deficient animals upon ER dysregulation, as a key effector suppressing polyQ toxicity. Over-expression of , but not other HSP70 family chaperones, is sufficient to rescue developmental arrest in polyQ-expressing embryos upon knock-down. Finally, we show that knock-down of , , or blocks the upregulation of in -deficient worms. Taken together, our findings support a model in which the loss of FIC-1-mediated AMPylation engages UPR signaling to upregulate cytosolic chaperone activity in response to polyQ toxicity.