title: Covalent ISG15 conjugation positively regulates the ubiquitin E3 ligase activity of parkin.
abstract: 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.
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
authors.forename: Eunju
authors.initials: E
authors.lastname: Im
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
authors.forename: Lang
authors.initials: L
authors.lastname: Yoo
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
authors.forename: Minju
authors.initials: M
authors.lastname: Hyun
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Shin
authors.affiliation: Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea kchung@yonsei.ac.kr.
authors.forename: Kwang Chul
authors.identifier: 0000-0003-4658-3849
authors.initials: KC
authors.lastname: Chung
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D041681:NIH 3T3 Cells; D010300:Parkinson Disease / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D016207:Cytokines; C402395:HERC5 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D014452:Ubiquitins; C074034:ISG15 protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008239:Lysine
keywords: E3 ligase; HERC5; ISG15; ISGylation; Parkinson's disease; parkin