A phosphoswitch at acinus-serine controls autophagic responses to cadmium exposure and neurodegenerative stress.

Neuronal health depends on quality control functions of autophagy, but mechanisms regulating neuronal autophagy are poorly understood. Previously, we showed that in starvation-independent quality control autophagy is regulated by acinus (acn) and the Cdk5-dependent phosphorylation of its serine (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of acinus-serine (acn-S437) phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an acn gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-acn levels. Cdk5-dependent phosphorylation of acn-S437 in animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Huntington's disease model. Consistent with previous findings that Cd inhibits PPM-type phosphatases, Cd exposure elevated acn-S437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd-induced cytotoxicity. Together, our data establish the acn-S437 phosphoswitch as critical integrator of multiple stress signals regulating neuronal autophagy.