Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41422-018-0056-0
Title: PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1–Parkin-mediated mitophagy
Authors: Wang L. 
Cho Y.-L. 
Tang Y.
Wang J. 
Park J.-E.
Wu Y. 
Wang C.
Tong Y. 
Chawla R. 
Zhang J. 
Shi Y. 
Deng S. 
Lu G.
Wu Y.
Tan H.W.-S. 
Pawijit P.
Lim G.G.-Y.
Chan H.-Y.
Zhang J.
Fang L.
Yu H. 
Liou Y.-C.
Karthik M. 
Bay B.-H. 
Lim K.-L. 
Sze S.-K.
Yap C.T. 
Shen H.-M. 
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Wang L., Cho Y.-L., Tang Y., Wang J., Park J.-E., Wu Y., Wang C., Tong Y., Chawla R., Zhang J., Shi Y., Deng S., Lu G., Wu Y., Tan H.W.-S., Pawijit P., Lim G.G.-Y., Chan H.-Y., Zhang J., Fang L., Yu H., Liou Y.-C., Karthik M., Bay B.-H., Lim K.-L., Sze S.-K., Yap C.T., Shen H.-M. (2018). PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1–Parkin-mediated mitophagy. Cell Res. : 1-16. ScholarBank@NUS Repository. https://doi.org/10.1038/s41422-018-0056-0
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. © 2018 IBCB, SIBS, CAS
Source Title: Cell Res.
URI: http://scholarbank.nus.edu.sg/handle/10635/150083
ISSN: 10010602
DOI: 10.1038/s41422-018-0056-0
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