Abstract
Ubiquitin-specific protease 30 (USP30) is a deubiquitinating enzyme (DUB) belonging to the USP subfamily, which was found localized in the mitochondrial outer membrane and peroxisomes owing to its unique transmembrane domain. Structural study revealed that USP30 employed a unique catalytic triad and molecular architecture to preferentially cleave the Lys6 linked ubiquitin chains. USP30 plays an essential role in several cellular events, such as the PINK1/Parkin-mediated mitophagy, pexophagy, BAX/BAK-dependent apoptosis, and IKKβ–USP30–ACLY-regulated lipogenesis/tumorigenesis, and is tightly regulated by post-translational modification including phosphorylation and mono-ubiquitination. Dysregulation of USP30 is associated with a range of physiological disorders, such as neurodegenerative disease, hepatocellular carcinoma, pulmonary disorders, and peroxisome biogenesis disorders. Nowadays, scientists and many biopharmaceutical companies are making much effort to explore USP30 inhibitors including natural compounds, phenylalanine derivatives, N-cyano pyrrolidines, benzosulphonamide, and other compounds. For the treatment of pulmonary disorders, the study in Mission Therapeutics of USP30 inhibitor is already in the pre-clinical stage. In this review, we will summarize the current knowledge of the structure, regulation, emerging physiological role, and target inhibition of USP30, hoping to prompt further investigation and understanding of it.
Highlights
Ubiquitin (Ub) is a small 76 amino acid-containing protein tag, which is critical in the aspect of regulating the protein destiny in cells (Ciechanover, 2003; Schwartz and Hochstrasser, 2003)
In recent years, emerging studies illustrated the role of Ubiquitin-specific protease 30 (USP30) from the molecular mechanism to its important physiological function
USP30 employed a unique catalytic triad (Cys77, His452 and Ser477) and molecular structure to preferential cleave Lys6 linked ubiquitin chains, which is different from the non-selectivity of other ubiquitin-specific protease (USP) members
Summary
Ubiquitin (Ub) is a small 76 amino acid-containing protein tag, which is critical in the aspect of regulating the protein destiny in cells (Ciechanover, 2003; Schwartz and Hochstrasser, 2003). Studies demonstrated that USP30 opposes the mitophagy caused by the PINK1/Parkin-mediated cascade of ubiquitination and phosphorylation under the mitochondrial depolarization status (Bingol et al, 2014). USP30 preferentially cleaves Lys6linked ubiquitin chains (Cunningham et al, 2015), and recent structural progress on either the hUSP30 or zUSP30 complexed with Lys6-di-Ub revealed the molecular mechanism for their preference cleavage of Lys6-linked Ub chains (Gersch et al, 2017; Sato et al, 2017). In vitro reconstitution experiment revealed the mono-ubiquitination of USP30 on Lys235, Lys289, and Lys310 by the phosphorylated Parkin, matching the ubiquitination sites previously found in cells (Bingol et al, 2014; Cunningham et al, 2015; Gersch et al, 2017) (Figure 1A). The key mitophagy signaling molecule PINK1 can regulate USP30 indirectly via phosphorylating the ubiquitin substrate (Wauer et al, 2015). USP30 knockout mice are viable and born with Mendelian ratios with no gross histological phenotypes
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