Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1.
Deubiquitinating enzymes (DUBs) are negative regulators of protein ubiquitination and play an important role in ubiquitin-dependent processes. Recent studies have found that diverse cellular mechanisms are employed to control the activity of DUBs. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a highly expressed neuronal DUB linked to Parkinson disease; however, little is known about its specific functions or modes of regulation. Here, we demonstrate that UCH-L1 is post-translationally modified by monoubiquitin in cells, at lysine residues near the active site. This modification restricts enzyme activity by preventing binding to ubiquitinated targets, and permanent monoubiquitination, as mimicked by a ubiquitin-UCH-L1 fusion, inhibits UCH-L1 in its capacity to increase free ubiquitin levels in cells. Interestingly, UCH-L1 catalyzes its own deubiquitination in an intramolecular manner, thereby regulating the lifetime of this modification. Our results illustrate monoubiquitination as a reversible regulatory mechanism for DUB activity involving auto-deubiquitination.
Meray
Robin K
RK
Department of Neurology, Harvard Medical School and Brigham and Women's Hospital, Cambridge, Massachusetts 02139, USA.
Lansbury
Peter T
PT
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D010300:Parkinson Disease / Q000201:enzymology*; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism*
C482860:UCHL1 protein, human; D025801:Ubiquitin; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases