USP13: Multiple Functions and Target Inhibition

Abstract

As a deubiquitination (DUB) enzyme, ubiquitin-specific protease 13 (USP13) is involved in a myriad of cellular processes, such as mitochondrial energy metabolism, autophagy, DNA damage response, and endoplasmic reticulum-associated degradation (ERAD), by regulating the deubiquitination of diverse key substrate proteins. Thus, dysregulation of USP13 can give rise to the occurrence and development of plenty of diseases, in particular malignant tumors. Given its implications in the stabilization of disease-related proteins and oncology targets, considerable efforts have been committed to the discovery of inhibitors targeting USP13. Here, we summarize an overview of the recent advances of the structure, function of USP13, and its relations to diseases, as well as discovery and development of inhibitors, aiming to provide the theoretical basis for investigation of the molecular mechanism of USP13 action and further development of more potent druggable inhibitors.

LncRNA FRMD6‐AS1/miR‐491‐5p/USP13 pathway attenuated ferroptosis and contributed to liver fibrosis

“…24,27,41 USP13 is a deubiquitinase that modulates cancer progression, immune inflammatory response, metabolism disorder. 28 Several studies have shown that USP13 exerted important functions in modulating lung fibrosis and ECM deposition. Knockdown of USP13 accelerated lung fibroblasts phenotypic changes and contributed to pulmonary fibrosis.…”

“…Ubiquitin-specific protease 13 (USP13) is a vital factor in innate immune responses, energy metabolism, autophagy, DNA damage response in different diseases, and can act as a tumor promoter in cancers. 28 Reports have found that USP13 was critical in the pathogenetic mechanism of pulmonary fibrosis, and knockdown of USP13 promoted lung fibroblasts phenotypic changes and contributes to pulmonary fibrosis. 29,30 Besides, USP13 overexpression reversed the repression of Spautin-1-induced autophagy and ferroptosis in cerebral ischemia-reperfusion injury.…”

Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin

“…Ataxin 3 has been reported to directly interact with Parkin and regulates its ubiquitylation [ 72 , 73 , 75 ]. Ataxin 3 has a preference for K63-linked Ub chains and plays an important role in DNA repair and endoplasmatic reticulum-associated degradation [ 72 ].…”

“…Ataxin 3 has been reported to directly interact with Parkin and regulates its ubiquitylation [ 72 , 73 , 75 ]. Ataxin 3 has a preference for K63-linked Ub chains and plays an important role in DNA repair and endoplasmatic reticulum-associated degradation [ 72 ]. The catalytic activity of Ataxin 3 is regulated via its N-terminal Josephin domain, whereas the C-terminal domain containing the Ub-interacting motif controls which interacts with different substates including Parkin [ 72 , 75 ].…”

“…Ataxin 3 has a preference for K63-linked Ub chains and plays an important role in DNA repair and endoplasmatic reticulum-associated degradation [ 72 ]. The catalytic activity of Ataxin 3 is regulated via its N-terminal Josephin domain, whereas the C-terminal domain containing the Ub-interacting motif controls which interacts with different substates including Parkin [ 72 , 75 ]. Mutations in Ataxin 3 have been associated with Machado-Joseph disease where Parkin degradation was accelerated via the autophagy pathway [ 73 , 75 ].…”