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

• Main Authors: Wang, Liming, Cho, Yik-Lam, Tang, Yancheng, Wang, Jigang, Park, Jung-Eun, Wu, Yajun, Wang, Chunxin, Tong, Yan, Chawla, Ritu, Zhang, Jianbin, Shi, Yin, Deng, Shuo, Lu, Guang, Wu, Yihua, Tan, Hayden Weng-Siong, Pawijit, Pornteera, Lim, Grace Gui-Yin, Chan, Hui-Ying, Zhang, Jingzi, Fang, Lei, Yu, Hanry, Liou, Yih-Cherng, Karthik, Mallilankaraman, Bay, Boon-Huat, Lim, Kah-Leong, Sze, Siu-Kwan, Yap, Celestial T., Shen, Han-Ming
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2020
• Subjects: Science::Biological sciences; PTEN-L; Neurodegenerative Disorders
• Online Access: https://hdl.handle.net/10356/137546
• Institution: Nanyang Technological University

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.