IndraLab

Statements

USP30 inhibits PRKN. 29 / 33
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"Our findings provided further verification explaining the functions of Parkin and USP30 in mitophagy and cell senescence, demonstrating that USP30 knockdown could alleviate d-gal-induced mitochondrial damage, and d-gal-promoted myocardial cell senescence by increasing the activity of Parkin.In conclusion, the findings of the present study demonstrated that silencing USP30 upregulated Parkin, resulting in the stimulation of mitophagy and deceleration of myocardial cell senescence (Fig. 6)."
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"The best evidence to date comes from analyzing USP30 which appears to antagonize Parkin function as evidenced by the fact that genetic inhibition of USP30 rescues Parkin deficient flies."
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"Several studies have reported that USP30 is a classic antagonist of Parkin ."
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"The E3 ligase Parkin ubiquitinates the membrane proteins on targeted mitochondria to initiate mitophagy, whereas USP30 antagonizes Parkin-dependent mitophagy by removing ubiquitin from Parkin substrates."
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"In cell systems that have been designed to overexpress Parkin, USP30 can restrict Parkin-dependent ubiquitylation of certain substrates and depolarization-induced mitophagy [76]."
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"However, USP30 overexpression antagonizes the activity of Parkin to sustain AKT/mTOR activity and inhibit apoptosis."
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"Genetic overexpression of USP30 removes the ubiquitin chains and blocks Parkin-driven mitophagy, whereas knockdown of USP30 promotes degradation of damaged mitochondria and exerts neuroprotective effe[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"On the other hand, inhibition of USP30 expression or activity could allow cells to overcome the defects of PINK1 and Parkin, and restore the clearance of impaired mitochondria (Bingol et al., 2014)."
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"Current therapeutic strategies primarily focus on blocking mitochondrial USP30, which antagonizes Parkin by removing ubiquitin from the mitochondrial surface."
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"Emerging promising molecules include selective inhibitor of the mitochondrial deubiquitinase, USP30 that negatively regulates PRKN-mediated mitophagy [132,200]."
| PMC
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"Notably, among them there are proteins, which are able to antagonise Parkin activity, such as the anti-apoptotic members of the Bcl-2 family Bcl-X L and Mcl-1, or the deubiquitinases USP30 ( Bingol et[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"USP30 inhibits apoptosis by stabilizing Parkin [39].2.3 Regulation of Signaling Pathways."
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"Parkin mediated effects are further regulated by de-ubiquitinating enzymes, such as USP30 and USP35, which reportedly de-ubiquitinate Parkin substrates to antagonize mitophagy [XREF_BIBR] or Parkin dependent cell death [XREF_BIBR]."
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"USP30 Inhibits PINK1/Parkin-Dependent Mitophagy by Deubiquitinating Mitochondrial Proteins."
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"Strikingly USP30 knockdown invivo could rescue the PINK1 or Parkin -/- phenotypes in Drosophila, indicating that the inhibition of USP30 could be therapeutically advantageous in patients with equivalent null mutations in these genes [XREF_BIBR]."
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"The OMM localized DUB ubiquitin specific processing proteases USP30 and USP15 antagonize PARKIN activity by cleaving ubiquitin chains on mitochondria."
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"For example, USP15, USP30, and USP35 are known to eliminate the ubiquitin- and parkin-mediated signals, consequently delaying or disrupting mitophagy (5)."
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"In contrast, a recent report demonstrated that in Drosophila the age dependent increase in mitophagy in both muscle and dopaminergic neurons is dependent on PINK1 and Parkin, and the knockdown of USP15 and USP30 rescues mitophagy in Parkin deficient organisms."
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"USP30, a transmembrane DUB localized on the mitochondrial outer membrane, antagonizes the function of Parkin by removal of ubiquitin chains from mitochondria [80]."
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"However, USP30 can also antagonize Parkin in the autophagy pathway ."
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"On one hand, overexpression of USP30 can block Parkin dependent accumulation of Ub chains on MOM proteins in response to depolarization, suggesting that USP30 directly antagonizes Parkin activity."
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"However, whether USP30 also comprises specificity at the level of primary ubiquitylation sites in MOM substrates, and the extent to which USP30 activity suppresses the PARKIN feed-forward activation mechanism via pS65-Ub has not been examined in more physiological systems such as neurons."
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"The regulation of USP30 activity is important, since hyperactivation of USP30 prevents Parkin from promoting removal of dysfunctional mitochondria (186, 187)."
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"USP8, USP14, USP15, USP30, USP33, and USP35 have been shown to antagonize Parkin activity [[92], [93], [94], [95], [96], [97]]."
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"Therefore, the activities of USP30 and USP15 in antagonizing Parkin would be expected to promote PD phenotypes [62]."
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"However, USP30 inhibits the E3 function of Parkin by removing K6-linked ubiquitin chains in mitochondria ( Bingol et al., 2014 ; Sato et al., 2017 )."
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"The overexpression of USP30 has been reported to inhibit the recruitment of Parkin to damaged mitochondria [11]."
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"Bingol et al. proposed that USP30 removes ubiquitin attached to damaged mitochondria via Parkin and blocks Parkin-driven mitochondrial phagocytosis."
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"In this regard, USP15 and USP30 were found to antagonize Parkin activity by competing for the common substrates on OMM."
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