Collective cell migration relies on PPP1R15-mediated regulation of the endoplasmic reticulum stress response

Collective cell migration is integral to many developmental and disease processes. Previously, we discovered that protein phosphatase 1 (Pp1) promotes border cell collective migration in the Drosophila ovary. We now report that the Pp1 phosphatase regulatory subunit dPPP1R15 is a critical regulator of border cell migration. dPPP1R15 is an ortholog of mammalian PPP1R15 proteins that attenuate the endoplasmic reticulum (ER) stress response. We show that, in collectively migrating border cells, dPPP1R15 phosphatase restrains an active physiological protein kinase R-like ER kinase- (PERK)-eIF2α-activating transcription factor 4 (ATF4) stress pathway. RNAi knockdown of dPPP1R15 blocks border cell delamination from the epithelium and subsequent migration, increases eIF2α phosphorylation, reduces translation, and drives expression of the stress response transcription factor ATF4. We observe similar defects upon overexpression of ATF4 or the eIF2α kinase PERK. Furthermore, we show that normal border cells express markers of the PERK-dependent ER stress response and require PERK and ATF4 for efficient migration. In many other cell types, unresolved ER stress induces initiation of apoptosis. In contrast, border cells with chronic RNAi knockdown of dPPP1R15 survive. Together, our results demonstrate that the PERK-eIF2α-ATF4 pathway, regulated by dPPP1R15 activity, counteracts the physiological ER stress that occurs during collective border cell migration. We propose that in vivo collective cell migration is intrinsically “stressful,” requiring tight homeostatic control of the ER stress response for collective cell cohesion, dynamics, and movement. [Display omitted] •dPPP1R15 disruption impairs border cell collective delamination and migration•dPPP1R15 is essential for tightly regulated front-directed protrusions•Normal collectively migrating border cells exhibit physiological ER stress•dPPP1R15 limits PERK-eIF2α-ATF4 ER stress response for border cell migration Precise control of endoplasmic reticulum (ER) stress ensures cell health. Chen and McDonald show that normal migrating border cells exhibit physiological ER stress that is restrained by dPPP1R15. This regulation prevents excessive activation of the PERK-p-eIF2α-ATF4 ER stress response pathway, ensuring effective collective border cell migration.