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      Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1.

      The Journal of Biological Chemistry
      Animals, COS Cells, Cercopithecus aethiops, Cysteine Endopeptidases, metabolism, Half-Life, Humans, Parkinson Disease, enzymology, Protein Processing, Post-Translational, physiology, Ubiquitin, Ubiquitin Thiolesterase

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          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.

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