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bioRxiv · 10.1101/2021.07.27.453988

A phospho-switch at Acinus-Serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress

Nandi, N.·Zaidi, Z.·Tracy, C.·Krämer, H.
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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 Huntingtons 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.

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Nandi, N., Zaidi, Z., Tracy, C., Krämer, H.. 2021-07-28. A phospho-switch at Acinus-Serine437 controls autophagic responses to cadmium exposure and neurodegenerative stress. https://doi.org/10.1101/2021.07.27.453988

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