Please use this identifier to cite or link to this item:
|Title:||PTEN-L is a novel protein phosphatase for ubiquitin dephosphorylation to inhibit PINK1–Parkin-mediated mitophagy||Authors:||Wang L.
|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|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
|s41422-018-0056-0.pdf||4.06 MB||Adobe PDF|
checked on Aug 19, 2019
WEB OF SCIENCETM
checked on Dec 24, 2018
checked on Aug 15, 2019
checked on Aug 15, 2019
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.