Research Group of Prof. Zheng Ying and Hongfeng Wang Publishes in Autophagy: Unveils PPP2/PP2A-Mediated LC3B Dephosphorylation Mechanism, Offering Theoretical Foundation for SCA12 Therapeutic Development

Post-translational modifications of mammalian Atg8-family proteins, including phosphorylation, regulate multiple steps in the autophagic process. Mechanistically, this study found 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. Importantly, this research revealed that overexpression of β2 isoform of PPP2R2B, 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. Overall, this research not only uncovers a mechanism by which protein dephosphorylation negatively regulates mitophagy but also provides insights into the pathogenesis of PPP2R2Bβ2-mediated SCA12. The research is the first to reveal that protein phosphatase PPP2/PP2A is the key regulator of autophagy protein LC3B dephosphorylation and elucidates its underlying mechanisms in neurodegenerative diseases.

PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis. Autophagy 2025. doi: 10.1080/15548627.2025.2572528
https://doi.org/10.1080/15548627.2025.2572528