USP30
Deubiquitinase USP30 is a mitochondria-localized deubiquitinase positioned on the outer mitochondrial membrane, where it removes ubiquitin from mitochondrial substrates and functions as a key negative regulator of mitochondrial quality control pathways[1][2]. Mechanistically, USP30 antagonizes the PINK1-Parkin ubiquitination cascade by reversing Parkin-mediated ubiquitination of outer mitochondrial membrane proteins, thereby limiting mitophagy initiation and progression[1][3][4]. Through this activity, USP30 establishes a regulatory threshold for ubiquitin signaling on damaged mitochondria and influences the accumulation of mitophagy-associated ubiquitin modifications[3][5]. In disease-relevant models, genetic depletion or inhibition of USP30 enhances mitochondrial clearance, restores mitophagy defects associated with impaired PINK1 or Parkin function, and improves mitochondrial integrity in experimental systems linked to Parkinson’s disease[1]. Beyond neurodegeneration, USP30-dependent regulation of mitophagy has also been implicated in cellular stress responses, mitochondrial dysfunction, and age-associated pathological processes[6]. Compared with other deubiquitinases involved in mitochondrial quality control, USP30 is distinguished by its localization to the outer mitochondrial membrane and its direct antagonism of the PINK1-Parkin pathway, making it a prominent target for mechanistic studies of mitophagy regulation[2][7]. For experimental applications, highly selective small-molecule USP30 inhibitors, including N-cyano pyrrolidine-based compounds, increase ubiquitination of mitochondrial substrates and serve as useful tools for investigating mitophagy signaling and mitochondrial homeostasis[3][5].
References:
- [1]. Bingol B, et al. The mitochondrial deubiquitinase USP30 opposes parkin-mediated mitophagy. Nature. 2014 Jun 19;510(7505):370-5. [Content Brief]
- [2]. Tsefou E, et al. Investigation of USP30 inhibition to enhance Parkin-mediated mitophagy: tools and approaches. Biochem J. 2021 Dec 10;478(23):4099-4118. [Content Brief]
- [3]. Jandke A, et al. Butyrophilin-like proteins display combinatorial diversity in selecting and maintaining signature intraepithelial γδ T cell compartments. Nat Commun. 2020 Jul 28;11(1):3769. [Content Brief]
- [4]. Pinho BR, et al. Targeting mitochondrial deubiquitinase USP30 to induce mitophagy in heteroplasmic mitochondrial diseases. Pharmacol Rep. 2026 Apr;78(2):519-534. [Content Brief]
- [5]. Rusilowicz-Jones EV, et al. Benchmarking a highly selective USP30 inhibitor for enhancement of mitophagy and pexophagy. Life Sci Alliance. 2021 Nov 29;5(2):e202101287. [Content Brief]
- [6]. Pan W, et al. Deubiquitinating enzyme USP30 negatively regulates mitophagy and accelerates myocardial cell senescence through antagonism of Parkin. Cell Death Discov. 2021 Jul 21;7(1):187. [Content Brief]
- [7]. Wang F, et al. USP30: Structure, Emerging Physiological Role, and Target Inhibition. Front Pharmacol. 2022 Mar 3;13:851654. [Content Brief]
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USP30 Related Products (5)
Related Products (5)
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CMPD-39
0 ImagesCMPD-39 is a selective non-covalent inhibitor of the ubiquitin-specific protease USP30 (IC50=~20 nM), with high selectivity over other DUB family members (1-100 μM). CMPD-39 inhibits the deubiquitinating activity of USP30, enhances the ubiquitination of mitochondrial proteins TOMM20 and SYNJ2BP; thus, CMPD-39 promotes phosphoubuitin accumulation, thereby accelerating mitochondrial autophagy (mitophagy) and peroxisomal autophagy (pexophagy). CMPD-39 significantly restores impaired mitochondrial function in dopaminergic neurons derived from Parkinson's disease patients.
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Q14
0 ImagesCat. No.: HY-P10416Purity: 98.51%Synonyms: Q14 peptideQ14 is a polypeptide derived from the USP30 (ubiquitin specific peptidase 30) transmembrane (TM) domain with the ability to inhibit the deubiquitination activity of USP30 (IC50=57.2 nM). Q14 reduces USP30 activity by inhibiting the interaction between the USP30 transmembrane domain and its catalytic domain. Q14 peptide contains the LC3 interaction region (LIR) motif, which enables it to bind to the LC3 and accelerate the formation of autophagosomes, thereby promoting mitophagy. Q14 can be used in the study of neurodegenerative diseases as well as mitochondrial quality control and cell metabolism.
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USP30-IN-2
0 ImagesCat. No.: HY-182553CAS No.: 2414580-72-4
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MT16-001
0 ImagesCat. No.: HY-182636CAS No.: 1895049-73-6MT16-001 is a cell-permeable UCHL1 inhibitor with an IC50 value of 580 nM. MT16-001 also exhibits considerable inhibitory activity against USP30, and shows selectivity for other UCH family deubiquitinases (DUBs) as well as the broader proteome. MT16-001 binds covalently to the cysteine residue at the active site of UCHL1, and forms covalent interactions with ALDH2, ALDH9A1 and GATD3A in intact cells. Meanwhile, as a cytotoxic agent, it displays a steep dose-response curve in human embryonic kidney cells. MT16-001 can be used for research on various cancers, liver fibrosis and pulmonary fibrosis.
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USP30-IN-20
0 ImagesCat. No.: HY-175826USP30-IN-20 is an orally active USP30 inhibitor (Kd = 1.61 μM, IC50 = 12.8 μM). USP30-IN-20 induces ferroptosis by promoting ubiquitination-mediated degradation of GPX4. USP30-IN-20 inhibits the proliferation, migration, invasion, and stemness of prostate cancer cells. USP30-IN-20 induces G0/G1 cell cycle arrest and ROS levels in prostate cancer cells. USP30-IN-20 exhibits significant anti-tumor efficacy in PC3 cell subcutaneous xenografts in mice. USP30-IN-20 can be used for the study of advanced prostate cancer.
