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USP14 inhibits Ubiquitin. 27 / 30
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"Ubiquitin specific protease-14 (USP14), a DUB reversibly associated with the proteasome, negatively regulates the activity of proteasomes by trimming ubiquitin chains on proteasome bound substrates."
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"USP14 prevents protein substrate degradation by blocking the ubiquitin chain and promoting protein degradation by activating proteases (Wang F. et al., 2021)."
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"In agreement with this data, deletion of the mouse ortholog USP14 causes a depletion of free ubiquitin and ataxic mice (ax J) that contain a mutant form of the Usp14 gene display a reduction in free monoubiquitin levels in the brain."
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"USP14 as a component of proteasome-associated deubiquitinating enzyme complex can eliminate ubiquitins from proteasome-bound substrates and inhibit the proteasome non-catalytically ( Chen et al ., 2018 ) ."
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"USP14 inhibits proteasome activity by trimming the ubiquitin chain on the substrate."
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"USP14 inhibits proteasomal degradation of ubiquitin–protein conjugates by trimming ubiquitin chains on protein substrates before their degradation ."
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"By separating ubiquitin from its conjugative target, Usp14 antagonizes this pathway of ubiquitin degradation."
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"The deubiquitinating enzyme Usp14 allosterically inhibits multiple proteasomal activities and ubiquitin independent proteolysis."
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"Thus, USF1 exacerbated atherosclerosis progression by transcriptional activation of USP14.As a deubiquitinating enzyme, USP14 eliminates ubiquitin to cause de-ubiquitination and stabilization of its target proteins (Kim and Goldberg 2017)."
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"Although PINK1/Parkin-mediated mitophagy has been well studied, no effective drug targeting this pathway has been employed for the treatment of neurodegenerative diseases.As a negative feedback mechan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Taken together, these data show that phosphorylation of USP14 by Akt is important for this kinase to negatively regulate the UPS in a ubiquitin dependent manner."
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"USP14 impedes degradation of ubiquitinated proteins by removing ubiquitin chains from its substrates, while it could promote protein degradation via increasing proteasome activation."
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"Toward the identification of small-molecule stimulators of the ubiquitin-proteasome system to enhance the clearance of deleterious proteins, the discovery that a proteasome associated deubiquitinating enzyme, USP14, inhibits proteasomal degradation of proteins by trimming off ubiquitin chains inspired a high-throughput screen to find inhibitors of USP14 activity [XREF_BIBR]."
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"USP14 is shown to inhibit the degradation of Ub–protein conjugates both in vitro and in cells by trimming Ub chains on substrates [122]."
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"By contrast, USP14 and UCHL5 are located further from the 20S core and antagonize degradation by removing Ub in a stepwise manner from the distal end, promoting substrate dissociation from the proteasome 17.The human genome encodes for approximately 90 DUBs, which fall into six classes 18, 19."
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"The deubiquitinating enzyme Usp14 allosterically inhibits multiple proteasomal activities and ubiquitin independent proteolysis."
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"Structural studies show that two surface loops BL1 and BL2 on free USP14 prevent active site binding to the C-terminus of ubiquitin."
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"In addition, USP14 inhibition with IU1 increased the extent of ubiquitin modification of UVRAG ( Figure 3 E), indicating that the cellular levels of UVRAG are actively controlled by the UPS and, possi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Hence, a more likely explanation for these genetic interactions between ubp6 Delta and the proteasome subunits is that association of Ubp6 with the mutant 26 S proteasomes stabilises these otherwise l[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The proximity of the two surface loops above the catalytic sites to the ubiquitin-binding groove prevents the C-terminus of Ub from binding to the active site of USP14, hence free USP14 exhibits lowered deubiquitinating activity [111]."
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"Conversely, USP14 might also activate proteolysis by degrading ubiquitin chains on target proteins and thereby enhance gate opening of the 20S proteasome."
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"The degradation of Ub itself is closely related to the activities of DUBs associated with the proteasome since the loss of USP14 (or Ubp6 in yeast) or UCH37 has been shown to trigger degradation of Ub along with its target substrates, leading to depletion of the free Ub pool XREF_BIBR - XREF_BIBR."
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"However, later work has shown that ubiquitin overexpression does not correct the ax J deficits in hippocampal short term plasticity, and that transgenic expression of a catalytically inactive form of USP14 in the nervous system mimics the neuromuscular phenotype observed in the ax J mice, but causes a only a modest reduction of free ubiquitin."
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"Therefore, inhibition of ubiquitin-specific peptidase (USP14) in mouse embryonic fibroblasts would promote TDP-43 clearance by maintaining ubiquitin chains [54]."
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"It has been reported that both USP14 and UCH37 prevent substrate degradation by removing ubiquitin chains and promoting proteasomal substrate dissociation."
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"Similarly, UbVs were generated with high affinity for USP14, which inhibited Ub signaling and cell survival in yeast [XREF_BIBR]."
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"Studies have shown that the binding of either full-length USP14 or its UBL domain alone represses multiple proteasomal activities through its DUB activity in an allosteric mechanism, whereas USP14 promotes the proteasomal degradation of ubiquitin-conjugated substrates once bound to a ubiquitin chain (Crosas et al., 2006; Hanna et al., 2006; Kim and Goldberg, 2017; Kim and Goldberg, 2018b)."
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