2. Academic Validation
  3. PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis

PPP2/PP2A-mediated dephosphorylation of LC3B links PINK1-PRKN/Parkin-mediated mitophagy to SCA12 pathogenesis

  • Autophagy. 2025 Oct 13:1-13. doi: 10.1080/15548627.2025.2572528.
Ningning Li 1,  Hongyu Hou 1,  Dan Su 1,  Bojun Yang 1,  Rui Ni 1,  Guoqiang Ma 1,  Shan Sun 1 2,  Qilian Ma 1 3,  Qiang Peng 1,  Siqian Chen 1 2,  Kin Yip Tam 2,  Hongfeng Wang 1 4,  Zheng Ying 1 4 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
  • 2 Faculty of Health Sciences, University of Macau, Macau, China.
  • 3 Department of Physiology & Medical Physics and Future-Neuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
  • 4 MOE Key Laboratory of Geriatric Diseases and Immunology, College of Pharmaceutical Sciences, Suzhou Medical College of Soochow University, Suzhou, China.
  • 5 Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Soochow University, Suzhou, China.
PMID: 41059761 DOI: 10.1080/15548627.2025.2572528
Abstract

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.Abbreviations: AO: antimycin A and oligomycin A; DFP: deferiprone; EGFP: enhanced green fluorescent protein; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; OPTN: optineurin; PINK1: PTEN induced kinase 1; PLA: proximity ligation assay; PPP2: protein Phosphatase 2; PPP2CA: protein Phosphatase 2 catalytic subunit alpha; PPP2CB: protein Phosphatase 2 catalytic subunit beta; PPP2R2Bβ2: protein Phosphatase 2 regulatory subunit B beta 2; PRKN/Parkin: parkin RBR E3 ubiquitin protein ligase; SCA12: spinocerebellar ataxia type 12; WT: wild type.

Keywords

Dephosphorylation; LC3B; PINK1-PRKN/Parkin-mediated mitophagy; PPP2/PP2A; PPP2R2Bβ2; mitochondrial quality control.

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