Journal Article

PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1–Parkin-mediated mitophagy

Tang, Yancheng, Shi, Yin, Wu, Yajun, Chan, Hui-Ying, Lu, Guang, Yu, Hanry, Yap, Celestial T., Wang, Liming, Shen, Han-Ming, Liou, Yih-Cherng, Fang, Lei, Wang, Jigang, Pawijit, Pornteera, Bay, Boon-Huat, Tan, Hayden Weng-Siong, Wang, Chunxin, Park, Jung-Eun, Lim, Grace Gui-Yin, Cho, Yik-Lam, Zhang, Jingzi, Lim, Kah-Leong, Chawla, Ritu, Karthik, Mallilankaraman, Deng, Shuo, Sze, Siu-Kwan, Zhang, Jianbin, Tong, Yan, Wu, Yihua

2018

Overview

Mitophagy is an important type of selective autophagy for specific elimination of damaged mitochondria. PTEN-induced putative kinase protein 1 (PINK1)-catalyzed phosphorylation of ubiquitin (Ub) plays a critical role in the onset of PINK1–Parkin-mediated mitophagy. Phosphatase and tensin homolog (PTEN)-long (PTEN-L) is a newly identified isoform of PTEN, with addition of 173 amino acids to its N-terminus. Here we report that PTEN-L is a novel negative regulator of mitophagy via its protein phosphatase activity against phosphorylated ubiquitin. We found that PTEN-L localizes at the outer mitochondrial membrane (OMM) and overexpression of PTEN-L inhibits, whereas deletion of PTEN-L promotes, mitophagy induced by various mitochondria-damaging agents. Mechanistically, PTEN-L is capable of effectively preventing Parkin mitochondrial translocation, reducing Parkin phosphorylation, maintaining its closed inactive conformation, and inhibiting its E3 ligase activity. More importantly, PTEN-L reduces the level of phosphorylated ubiquitin (pSer65-Ub) in vivo, and in vitro phosphatase assay confirms that PTEN-L dephosphorylates pSer65-Ub via its protein phosphatase activity, independently of its lipid phosphatase function. Taken together, our findings demonstrate a novel function of PTEN-L as a protein phosphatase for ubiquitin, which counteracts PINK1-mediated ubiquitin phosphorylation leading to blockage of the feedforward mechanisms in mitophagy induction and eventual suppression of mitophagy. Thus, understanding this novel function of PTEN-L provides a key missing piece in the molecular puzzle controlling mitophagy, a critical process in many important human diseases including neurodegenerative disorders such as Parkinson’s disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 14 / 631/80/39/2348 / 631/80/458/1733 / 82 / 82/1 / Amino acids / Autophagy / Biomedical and Life Sciences / Cell Biology / Damage prevention / Dephosphorylation / Homology / Kinases / Life Sciences / Mitochondria / Mitophagy / N-Terminus / Neurodegenerative diseases / Parkin protein / Parkinson's disease / Phagocytosis / Phosphatase / Phosphorylation / Protein phosphatase / Proteins / PTEN protein / PTEN-induced putative kinase / Tensin / Translocation / Ubiquitin / Ubiquitin-protein ligase