Volume 28 Issue 8, August 2018: 787-802 | Open Access
ORIGINAL ARTICLES
PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1–Parkin-mediated mitophagy
Liming Wang 1, Yik-Lam Cho 1, Yancheng Tang 2, Jigang Wang 1, Jung-Eun Park 3, Yajun Wu 4, Chunxin Wang 5, Yan Tong 6, Ritu Chawla 1,Jianbin Zhang 1,7, Yin Shi 1, Shuo Deng 1, Guang Lu 1
, Yihua Wu 8, Hayden Weng-Siong Tan 1,9, Pornteera Pawijit 1, Grace Gui-Yin Lim 10,
Hui-Ying Chan 1,9, Jingzi Zhang 11, Lei Fang 11, Hanry Yu 1,12,13, Yih-Cherng Liou 6, Mallilankaraman Karthik 1, Boon-Huat Bay 4
,
Kah-Leong Lim1,10, Siu-Kwan Sze 3
, Celestial T. Yap1 and Han-Ming Shen1,9
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; 2School of Chinese Medicine, Hong Kong Baptist University,
Kowloon Tong, Hong Kong, China; 3School of Biological Sciences, Nanyang Technological University, Singapore, Singapore; 4Department of Anatomy, National University of
Singapore, Singapore, Singapore; 5Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health,
Bethesda, MD 20892, USA; 6Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore, Singapore; 7Department of Oncology, Clinical
Research Institute, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China; 8Department of Toxicology, Zhejiang University School of Public Health, Hangzhou, Zhejiang, China; 9Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore,
Singapore; 10 National Neuroscience Institute, Singapore, Singapore; 11Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, Medical School of Nanjing University, Nanjing, Jiangsu, China; 12Mechanobiology Institute, National University of Singapore, Singapore, Singapore and 13Institute of Bioengineering and Nanotechnology,
A*STAR, Singapore, Singapore
Correspondence: Correspondence: Han-Ming Shen (phsshm@nus.edu.sg)
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.
https://doi.org/10.1038/s41422-018-0056-0
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