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 (acn) 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-serine437 (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 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 acn-S437 phosphorylation which was necessary for increased neuronal autophagy and protection against Cd2+-induced cytotoxicity. Together, our data establish the acn-S437 phosphoswitch as critical integrator of multiple stress signals regulating neuronal autophagy.
Highlights
A key process for maintaining cellular fitness is autophagy, here short for macroautophagy (Fleming and Rubinsztein, 2020; Menzies et al, 2015)
We previously identified Acinus (Acn) as a regulator of starvation-independent quality control autophagy in Drosophila (Haberman et al, 2010; Nandi et al, 2014, 2017)
RNAi screen of the 37 non CTD-type serine-threonine phosphatases encoded in the Drosophila genome (Supplementary File 1)
Summary
A key process for maintaining cellular fitness is autophagy, here short for macroautophagy (Fleming and Rubinsztein, 2020; Menzies et al, 2015). Elevated basal autophagy can successfully reduce the polyQ load in models of Huntington’s disease or spinocerebellar ataxia type 3 (SCA3) and reduce neurodegeneration (Bilen and Bonini, 2007; Jaiswal et al, 2012; Nandi et al, 2014, 2017; Ravikumar et al, 2004). Both modes of autophagy use core autophagy proteins to initiate the generation of isolation membranes ( known as phagophores), promote their growth to autophagosomes, and promote their fusion with lysosomes or late endosomes to initiate degradation of captured content (Mizushima, 2017). The rapid induction of autophagy in response to nutrient deprivation is well described (Galluzzi et al, 2017), much less is known about the modulation of basal levels of autophagy in response to cellular stress
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