A phosphoswitch at acinus-serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress

Abstract

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 serine437 (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 serine437 in nil1 animals elevates neuronal autophagy and reduces the accumulation of polyQ proteins in a Drosophila Huntington's disease model. Consistent with previous findings that Cd2+ inhibits PPM-type phosphatases, Cd2+-exposure elevated Acinus-serine437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the Acinus-S437 phospho-switch as critical integrator of multiple stress signals regulating neuronal autophagy.

Activation loop phosphorylation of Cdk11 is restrained by PNUTS-PP1 and regulates Cdk11 activity and function

“…Amongst these proteins, we observed a 1.7-fold increase (P<0.01) in phosphorylation of the splicing factor Acinus at Ser 437 in PNUTS WT compared to PNUTS W726A IPs. Acinus pSer 437 was previously identified as a putative PP1 substrate in a screen for genetic modifiers of acinus overexpression [46]. Notably, we did not identify differential phosphorylation of Sf3b1.…”