Ningning Li, Hongyu Hou, Dan Su, Bojun Yang, Ruiqing Ni, Guoqiang Ma, Shan Sun, Qilian Ma, Qiang Peng, Siqian Chen, Kin Yip Tam, Hongfeng Wang, Zheng Ying
Atg8-family proteins are autophagosome-associated proteins and play important roles in macroautophagy/autophagy, a conserved process for degrading defective or excessive cellular components. Post-translational modifications of mammalian Atg8-family proteins, including phosphorylation, regulate multiple steps in the autophagic process. In this context, several Atg8-family protein-associated kinases have been found to regulate autophagy, yet the phosphatases in the dephosphorylation of Atg8-family proteins remain unknown. Here, we report that the heterotrimeric PPP2/PP2A (protein phosphatase 2) is a novel regulator in modulating LC3B dephosphorylation. Mechanistically, we find that PPP2-mediated LC3B dephosphorylation reduces the interaction between LC3B and the mitophagy receptor OPTN, thereby impeding the mitochondrial recruitment of phagophores during PINK1-PRKN/Parkin-mediated mitophagy. Interestingly, we find that overexpression of the β2 isoform of PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta; PPP2R2Bβ2), which mimics the spinocerebellar ataxia type 12 (SCA12) pathological condition, harms neuronal survival by enhancing PPP2-mediated LC3B dephosphorylation and reducing mitochondrial recruitment of phagophores upon mitochondrial damage. Importantly, pharmacological induction of mitophagy by the small molecule compound deferiprone (DFP) relieves PPP2R2Bβ2-mediated neuronal toxicity. Overall, our results not only uncover a mechanism by which protein dephosphorylation negatively regulates mitophagy but also provide insights into the pathogenesis of PPP2R2Bβ2-mediated SCA12.