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Proteasome binds USP14. 51 / 61
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"Moreover, the UBL domain is not strictly essential for binding to proteasomes as the USP domain maintains interactions with the OB ring of RPT subunits, in particular with Rpt1 [ xref , xref ], and indeed, truncated USP14 lacking its N-terminal UBL can associate with proteasomes [ xref , xref ]."
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"While USP14 can be found both free and bound to the proteasome, its catalytic activity has only been observed when associated with the proteasome [XREF_BIBR]."
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"Two additional DUBs, USP14 and UCHL5 (also known as and hereafter referred to as UCH37), also associate with the proteasome, although their precise roles are unclear (D'Arcy and Linder, 2012; Komander and Rape, 2012; Lee et al., 2011)."
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"Of note, the recruitment of USP14 to the proteasome was concomitantly reduced in TRIM11 overexpressing cells."
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"In the hippocampus, loss of Usp14 binding to the proteasome results in higher degradation rates that interfere with presynaptic formation, which can be rescued by overexpression of a catalytically inactive mutant 32."
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"Such inducible recruitment of USP14 to the proteasome may underlie the cytoprotective effects of USP14 inhibitors observed under some stress conditions."
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"The effect of USP14 aptamers on the interaction of USP14 with the proteasome was investigated using proteasome affinity pulldown assays."
26041011
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"In contrast to the association of Usp14, with the proteasome, the binding of its UBL domain alone increases coordinately the proteasome‘s three peptidase activities, which strongly suggests enhanced gate opening into the 20S particle."
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"Regarding the structure of proteasome bound to USP14, the USP14-Uba1 complex binds to the periphery of the oligosaccharide-binding (OB) ring, close to Rpn1, whereas the active site of USP14 is located in the axial channel of the OB ring."
35069211
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"However, recent studies have shown that, by contrast, upon chemical inhibition of the proteasome-bound DUB Usp14, the degradation of aggregation-prone substrates in mammalian tissue culture cells significantly increased [65]"
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"The binding of USP14 to the 26S proteasome was monitored by western blotting using an antibody against USP14 (Bethyl Laboratories, Inc)."
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"For instance, proteasome-bound USP14 protein was found to interact with molecular chaperone Hsc70 to modulate autophagy in neuroblastoma cells."
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"Uch37 and Usp14 associate reversibly with the proteasome, whereas Rpn11 is a stoichiometric subunit XREF_BIBR."
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"Consistent with the in vivo interaction between USP14 and the proteasome [5], we observed USP14EYFP predominantly in the cytoplasm, though we also noticed fluorescence in the nucleus (Figure 6C, lower left panel)."
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"It was initially believed that the presence of DUBs at the proteasome (such as Uch37/UchL5 and Usp14) would promote the degradation of proteins through facilitating substrate processing (see also the next section)"
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"In the most well-known example, the three DUBs, RPN11, USP14, and UCHL5, bind to the proteasome to deubiquitinate proteins substrates destined to degradation, thus recycling the ubiquitin molecules (99)."
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"Furthermore, this reconstituted system has enabled a high-throughput screening method for small-molecules that specifically inhibit proteasome bound USP14."
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"USP14 binding to proteasomes."
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"Interestingly, Chueh-Ling Kuo in our lab has shown that the presence of ubiquitinated proteins promotes the binding of free Usp14 to the proteasome, from which it dissociates when the ubiquitinated substrates are hydrolyzed [ xref ]."
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"It was once widely assumed that proteasome-bound USP14 progressively shortens the chains, one ubiquitin moiety at a time, from the substrate distal tip—the so called “distal chain trimming model” [ xref , xref ]."
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"IU1 was identified as an inhibitor of the proteasome bound Usp14 from a screen of 63,052 small molecules [XREF_BIBR]."
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"However, while GABA A Rs are enriched at the plasma membrane (P2), Usp14 binds to the proteasome and is consequently enriched in fraction P4 (XREF_FIG)."
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"The first three protocols describe the assays and steps for small-molecule inhibitor screening of USP14 : the DUB assay for proteasome bound USP14 (Basic Protocol 1), the HTS procedure for identifying small molecule inhibitors of USP14 (Basic Protocol 2), and post-HTS analysis to identify selective USP14 inhibitors (Basic Protocol 3)."
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"Activation of Ubp6 is unlikely to be peculiar to yeast since, in mammalian cell extracts, only proteasome bound Usp14 (the Ubp6 homolog) is active and can be labeled by UbVS (A.B. and H.P., unpublishe[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Overexpression of mutant USP14-W58A disrupted the interaction of USP14 with the 26S proteasome, while enhanced the binding of USP14 to the HSC70 chaperone and GABARAP autophagic protein ( xref )."
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"A primary regulatory checkpoint is the removal of ubiquitin chains from substrates by the deubiquitylating enzyme ubiquitin-specific protease 14 (USP14), which reversibly binds the proteasome and confers the ability to edit and reject substrates."
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"Among them, PSMD2 appeared to be the most abundant, consistent with the previous finding that USP14 binds to the proteasome via PSMD2 (ref."
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"Take for example, the other non-essential cysteine-dependent DUB that associates with the proteasome—USP14."
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"USP14 dynamically associates with the proteasome [ xref ]."
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"USP14, a DUB of the cysteine protease class, interacts reversibly with the proteasome [ xref , xref , xref , xref ] and it cleaves the ubiquitin chain off the targeted protein before degradation by the proteasome [ xref , xref ], thereby inhibiting the degradation of ubiquitin-protein conjugates in vitro and in vivo [ xref ]."
| PMC
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"For instance, proteasome-bound USP14 protein was found to interact with molecular chaperone Hsc70 to modulate autophagy in neuroblastoma cells."
32679806
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"On the other hand, it directly enhances the proteasome activity by interacting with the ubiquitin-like (UBL) domain of ubiquitin-specific protease 14 (also called USP14, which removes ubiquitin chains from substrates) which deterred the interaction between USP14 and the 19S subunit of the proteasome ( xref )."
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"Binding of USP14 or its yeast ortholog, UBP6, to the proteasome activates the catalytic activity of the DUB through an unknown mechanism XREF_BIBR."
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"Combining this with the fact that UBLCP1 is involved in proteasome assembly while USP14 binds to proteasome holoenzyme to remove the ubiquitin chain [XREF_BIBR, XREF_BIBR], we speculate that UBLCP1 and USP14 bind to the proteasome at different time windows."
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"Interestingly, a recent cryo-EM structure of USP14-bound human proteasome reveals that the Ins-1 loop of RPN11 adopts a more extended and flexible conformation compared to those found in USP14-free S1 and S2 states ( xref C, panels (a)–(c)) [ xref ]."
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"The p97 proteome also contained many proteasome subunits, but not the proteasome‐associated DUBs Rpn11/PSMD14, Ubp6/USP14 or UCH37/UCHL5 (Collins & Goldberg, 2017)."
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"Based on this rationale, we developed a high-throughput screening (HTS) method to identify inhibitors of proteasome bound USP14."
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"However, recent studies have shown that, by contrast, upon chemical inhibition of the proteasome bound DUB Usp14, the degradation of aggregation-prone substrates in mammalian tissue culture cells significantly increased [XREF_BIBR]."
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"In 2010, Finley and colleagues have identified IU1, the first highly selective inhibitor of proteasome-bound USP14 by ubiquitin-7-amido-4-methylcoumarin (Ub-AMC) hydrolysis assay-based high-throughput screening ( xref ) [ xref ]."
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"17 Of the three, USP14 and UCHL5 reversibly associate with the proteasome, whereas the third, RPN11 and POH1, is an intrinsic component of the lid subcomplex of the 19S cap."
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"In agreement with this, a highly selective inhibitor of USP14, IU1, (IC50 of Ub-AMC hydrolysis by proteasome bound USP14 is 4.7 +/- 0.7 muM), enhanced the destruction of several important proteasome substrates (Tau, TDP-43) involved in the development of neurodegenerative diseases [XREF_BIBR]."
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"Three different deubiquitinating enzymes (DUBs) are associated to the human proteasome, PSMD14/RPN11, USP14 and UCH37/UCHL5."
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"It was once widely assumed that proteasome bound USP14 progressively shortens the chains, one ubiquitin moiety at a time, from the substrate distal tip -- the so called " distal chain trimming model " [XREF_BIBR, XREF_BIBR]."
32726943
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"TRIM11 increases proteasome activity through binding to proteasome and USP14 [ xref ]."
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"We used NAC, a thiol containing compound, to block the active site of auranofin and found NAC recovers most auranofin mediated DUB inhibition to purified 26S proteasome, which confirms the computational model results that auranofin targets proteasome associated UCHL5 and USP14."
26097878
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"As shown in our previous publications ( xref ; xref ; xref ), we observed an increase in the levels of USP14 bound to proteasomes isolated from the TgUSP14 and TgUSP14CA mice as well as a decrease in the levels of USP14 on theax J proteasomes ( xref )."
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"For example, the first highly selective proteasome-bound USP14 inhibitor uu1(ubiquitin-7-amino-4-methylcoumarin, ub-amc) was identified by high-throughput screening of Ub-amc (161) ."
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"Accordingly, binding of Usp14 to the proteasome is thought to be necessary for efficient hydrolyse activity of Usp14 XREF_BIBR, XREF_BIBR."
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"Regarding the structure of proteasome bound to USP14, the USP14-Uba1 complex binds to the periphery of the oligosaccharide-binding (OB) ring, close to Rpn1, whereas the active site of USP14 is located in the axial channel of the OB ring."
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"As described above, recent cryo-EM data suggest that the Ubp6 and USP14 bound proteasome strongly favors the S2 state conformation, in which the ubiquitin charged catalytic domain of Ubp6 and USP14 makes stable contacts with the base RPT ring [XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"Unlike the Rpn11 and UCH37 DUBs, which are two constituent proteasome subunits, the USP14 interaction with the proteasome is reversible [XREF_BIBR]."
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