Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the pars compacta of the substantia nigra and accumulation of ubiquitinated proteins in aggregates called Lewy bodies. Several mutated genes have been found in familial PD patients, including SNCA (α-synuclein), PARK2 (parkin), PINK1, PARK7 (DJ-1), LRRK2 and ATP13A2. Many pathogenic mutations of PARK2, which encodes the ubiquitin E3 ligase parkin, result in loss of function, leading to accumulation of parkin substrates and consequently contributing to dopaminergic cell death. ISG15 is a member of the ubiquitin-like modifier family and is induced by stimulation with type I interferons. Similar to ubiquitin and ubiquitination, covalent conjugation of ISG15 to target proteins (ISGylation) regulates their biochemical properties. In this study, we identified parkin as a novel target of ISGylation specifically mediated by the ISG15-E3 ligase HERC5. In addition, we identified two ISGylation sites, Lys-349 and Lys-369, in the in-between-ring domain of parkin. ISGylation of these sites promotes parkin's ubiquitin E3 ligase activity by suppressing the intramolecular interaction that maintains its autoinhibited conformation and increases its cytoprotective effect. In conclusion, covalent ISG15 conjugation is a novel mode of modulating parkin activity, and alteration in this pathway may be associated with PD pathogenesis.
Bibliographical noteFunding Information:
This research was supported by grants from the National Research Foundation of Korea (NRF) (2014M3C7A1064545 to K.C.C.) funded by the Ministry of Science, ICT and Future Planning (MSIP), Republic of Korea, and from the Korea Healthcare Technology R&D Project (HI14C0093 to K.C.C.) through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea. This work was also supported in part by NRF grant (2015R1A2A2A01003080 to K.C.C.), by the Yonsei University Research Fund of 2014 (2014-12-0134 to E.I.) and by Yonsei University Future-leading Research Initiative of 2015 (2015-22-0055 to K.C.C.).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)