A phospho-switch at Acinus-Serine ⁴³⁷ 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 Drosophila starvation-independent quality control autophagy is regulated by Acinus and the Cdk5-dependent phosphorylation of its serine ⁴³⁷ (Nandi et al., 2017). Here, we identify the phosphatase that counterbalances this activity and provides for the dynamic nature of Acinus-S437 phosphorylation. A genetic screen identified six phosphatases that genetically interacted with an Acinus gain-of-function model. Among these, loss of function of only one, the PPM-type phosphatase Nil (CG6036), enhanced pS437-Acinus levels. Cdk5-dependent phosphorylation of Acinus serine ⁴³⁷ in nil ¹ animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington’s disease model. Consistent with previous findings that Cd ²⁺ inhibits PPM-type phosphatases, Cd ²⁺ -exposure elevated Acinus-serine ⁴³⁷ phosphorylation which was necessary for increased neuronal autophagy and protection against Cd ²⁺ -induced cytotoxicity. Together, our data establish the Acinus- S437 phospho-switch as critical integrator of multiple stress signals regulating neuronal autophagy.