Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/137546
Title: PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1-Parkin-mediated mitophagy
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
Keywords: Science::Biological sciences
Issue Date: 2018
Source: Wang, L., Cho, Y.-L., Tang, Y., Wang, J., Park, J.-E., Wu, Y., … Shen, H.-M. (2018). PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit pink1–parkin-mediated mitophagy. Cell Research, 28(8), 787-802. doi:10.1038/s41422-018-0056-0
Journal: Cell Research 
Abstract: 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.
URI: https://hdl.handle.net/10356/137546
ISSN: 1001-0602
DOI: 10.1038/s41422-018-0056-0
Rights: © 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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