caa a22 4500 606175261 CHVBK 20210128100742.0 cr unu---uuuuu 210128e20150501xx s 000 0 eng 10.1007/s00018-014-1781-2 doi (NATIONALLICENCE)springer-10.1007/s00018-014-1781-2 Parkin-mediated K63-polyubiquitination targets ubiquitin C-terminal hydrolase L1 for degradation by the autophagy-lysosome system [Elektronische Daten] [Jeanne McKeon, Di Sha, Lian Li, Lih-Shen Chin] Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a key neuronal deubiquitinating enzyme which is mutated in Parkinson disease (PD) and in childhood-onset neurodegenerative disorder with optic atrophy. Furthermore, reduced UCH-L1 protein levels are associated with a number of neurodegenerative diseases, whereas up-regulation of UCH-L1 protein expression is found in multiple types of cancer. However, very little is known about how UCH-L1 protein level is regulated in cells. Here, we report that UCH-L1 is a novel interactor and substrate of PD-linked E3 ubiquitin-protein ligase parkin. We find that parkin mediates K63-linked polyubiquitination of UCH-L1 in cooperation with the Ubc13/Uev1a E2 ubiquitin-conjugating enzyme complex and promotes UCH-L1 degradation by the autophagy-lysosome pathway. Targeted disruption of parkin gene expression in mice causes a significant decrease in UCH-L1 ubiquitination with a concomitant increase in UCH-L1 protein level in brain, supporting an in vivo role of parkin in regulating UCH-L1 ubiquitination and degradation. Our findings reveal a direct link between parkin-mediated ubiquitin signaling and UCH-L1 regulation, and they have important implications for understanding the roles of these two proteins in health and disease. Springer Basel, 2014 Parkinsonism nationallicence Ubiquitin nationallicence Lysine 63-linked polyubiquitination nationallicence Autophagy nationallicence Lysosome nationallicence UCH-L1 : Ubiquitin carboxyl-terminal hydrolase L1 nationallicence UPS : Ubiquitin proteasome system nationallicence DUB : Deubiquitinating enzyme nationallicence UBL : Ubiquitin-like domain nationallicence PD : Parkinson disease nationallicence ARJP : Autosomal recessive juvenile parkinsonism nationallicence RING : Really interesting new gene nationallicence IBR : In-between RING-finger domain nationallicence PKC : C-terminal parkin nationallicence PKN : N-terminal parkin nationallicence McKeon Jeanne Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut Sha Di Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut Li Lian Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut Chin Lih-Shen Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut Cellular and Molecular Life Sciences Springer Basel 72/9(2015-05-01), 1811-1824 1420-682X 72:9<1811 2015 72 18 https://doi.org/10.1007/s00018-014-1781-2 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00018-014-1781-2 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- McKeon Jeanne Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Sha Di Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Li Lian Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut NATIONALLICENCE 700 1- Chin Lih-Shen Department of Pharmacology, Emory University School of Medicine, 30322, Atlanta, GA, USA aut NATIONALLICENCE 773 0- Cellular and Molecular Life Sciences Springer Basel 72/9(2015-05-01), 1811-1824 1420-682X 72:9<1811 2015 72 18