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OTUD4 binds USP7. 50 / 50
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"Our domain mapping results indicate that the TRAF domain of USP7 mediated the interaction between USP7 and OTUD4."
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"Based on our findings, we propose the development of a peptide or peptide-like inhibitors to disrupt the interaction between OTUD4 and USP7 as a potential antiviral strategy."
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"Disrupting the OTUD4-USP7 deubiquitinase complex to suppress herpesvirus replication: a novel antiviral strategy."
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"Domain mapping experiments indicated that the N-terminal region of OTUD4 (1-425aa) interacted with USP7 ( xref )."
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"Notably, knockdown of USP7 in OTUD4-depleted cells could not further reduce KSHV progeny virion production ( xref ), suggesting that the OTUD4-USP7 axis plays a critical role in KSHV lytic reactivation."
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"Characterization of ALKBH3 interacting proteins show that USP7 and USP9x associate with another DUB OTU deubiquitinase 4 (OTUD4) to form a protein complex that deubiquitinates ALKBH3 [XREF_BIBR]."
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No evidence text available
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No evidence text available
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No evidence text available
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"Here, we developed a peptide, p8, which effectively disrupts the interaction between OTUD4 and USP7, leading to decreased abundance of the key viral transcription factor, RTA, and suppression of murine herpesvirus replication in vivo."
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"However, directly inhibiting transcriptional regulators like RTA remains highly challenging.In our previous studies, we discovered that the deubiquitinase (DUB) complex OTUD4-USP7 plays a critical role in KSHV lytic replication [27]."
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"Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies."
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"These findings not only reveal the critical role of the OTUD4-USP7 complex in gamma-herpesviruses infection, but also highlight the broader potential of targeting host factors involved in viral replication."
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"Given our findings that OTUD4 recruits USP7 to promote the deubiquitylation and stabilization of RTA, facilitating KSHV lytic replication [27], we hypothesized that disrupting the interaction between OTUD4 and USP7 might inhibit KSHV lytic replication."
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"To test this hypothesis, we aimed to design a peptide to block the interaction between OTUD4 and USP7, thereby promoting RTA degradation to curb KSHV lytic replication."
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"Collectively, these data indicate that the rationally designed OTUD4-derived peptide p8, which binds to USP7, shows promising antiviral activity against KSHV lytic replication."
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"P8 Disrupts the USP7-OTUD4 complex."
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"Our study not only unveils the mechanism by which KSHV exploits the OTUD4-USP7 deubiquitinases to enhance lytic reactivation but also provides insights into the development of novel antiviral therapeutic strategies targeting host deubiquitinase complexes."
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"Our studies thus far suggest that p8 disrupts the USP7-OTUD4 complex to repress KSHV lytic replication."
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"To elucidate the mechanism by which p8 interferes with the interaction between OTUD4 and USP7, we first utilized AlphaFold3 to predict the complex structure of the USP7-TRAF domain with p8 [30], given the availability of numerous crystal structures of the USP7-TRAF domain [31–36]."
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"Our previous work revealed that the OTUD4-USP7 DUB complex plays a crucial role in KSHV lytic reactivation."
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"Targeting the OTUD4-USP7 complex represses KSHV lytic replication."
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"Here, we developed a peptide, p8, which effectively disrupts the interaction between OTUD4 and USP7, leading to decreased abundance of the key viral transcription factor, RTA, and suppression of murine herpesviruses replication in vivo."
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"These findings underscore the OTUD4-USP7 DUB complex as a promising host-targeting antiviral therapeutic target for the treatment of KSHV-associated malignancies."
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"Our domain mapping results indicate that the TRAF domain of USP7 mediated the interaction between USP7 and OTUD4."
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"Next, we employed proximity ligation assay (PLA) to examine the impact of p8 on the interaction between OTUD4 and USP7 during viral infection."
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"Our previous study revealed that KSHV hijacks the OTUD4-USP7 complex to facilitate lytic reactivation [27]."
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"Our results indicate that p8 did not affect the interactions between USP7 and MDM2, p53, or ICP0 (S2B-S2D Figs), suggesting that p8 specifically disrupts the interaction between OTUD4 and USP7."
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"These findings indicate that OTUD4 interacts with USP7 via the Asp164 and Trp165 residues of the USP7-TRAF domain, and that p8 disrupted the OTUD4-USP7 complex by specifically targeting the binding interface between OTUD4 and USP7."
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"Together, our study reveals a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies."
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"By contrast, during KSHV lytic reactivation, the OTUD4-USP7 axis is required to stabilize K-RTA and promote viral replication."
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"Therefore, we hypothesize that disrupting the interaction between OTUD4 and USP7 would repress KSHV lytic reactivation."
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"Given that p8 specifically disrupts the interaction between OTUD4 and USP7, and that the OTUD4-USP7 complex is critical for maintaining RTA stability [27], we hypothesized that p8 treatment promotes RTA degradation to repress KSHV lytic replication."
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"These data indicate that the antiviral activity of p8 against KSHV relies on the OTUD4-USP7 complex.Previously, we identified the C-terminal FRD motif of RTA as crucial for recruiting the OTUD4-USP7 complex, and generated a KSHV-RTA-3A mutant by introducing F689A/R690A/D691A triple mutations into KSHV genome [27]."
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"These data indicate that p8 reduces RTA level by disrupting the interaction between OTUD4 and USP7, thereby repressing KSHV lytic reactivation."
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"Based on our findings, we propose the development of a peptide or peptide-like inhibitors to disrupt the interaction between OTUD4 and USP7 as a potential antiviral strategy."
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"Through screening OTUD4-derived peptides, we identified a peptide, p8, which effectively blocks the interaction between OTUD4 and USP7 and suppresses the replication of both KSHV and MHV68."
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"Our study provides proof-of-principle that disrupting the OTUD4-USP7 complex effectively suppresses the replication of both KSHV and MHV68."
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"Here, we present a prominent example in which a designed peptide specifically disrupts the interaction between OTUD4 and USP7 to exert potent antiviral activity."
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"Such inhibitors could specifically target the OTUD4-USP7 axis, which is critical for KSHV lytic reactivation while sparing the other vital functions of USP7."
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"In summary, we have developed an antiviral peptide inhibitor, p8, which effectively disrupts the interaction between OTUD4 and USP7, leading to decreased RTA levels and suppressing KSHV replication."
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No evidence text available
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"Whether OTUD4-USP7 and the proposed antiviral strategy affect other herpesviruses including MHV68 and EBV warrants further investigation."
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"Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed to develop new antiviral therapies."
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"Thank you very much for submitting your manuscript "Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases" for consideration at PLOS Pathogens."
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"The identification of K-Rta K218 as the major ubiquitination site for OTUD4-USP7 is an impressive finding."
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"To further elucidate the role of the OTUD4-USP7 axis in regulating K-Rta ubiquitination, the author should contemplate overexpressing USP7 in both parental and OTUD4-depleted cells, in order to show the inhibitory function of USP7 in K-Rta ubiquitination."
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"We are pleased to inform you that your manuscript 'Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases' has been provisionally accepted for publication in PLOS Pathogens."
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"We are delighted to inform you that your manuscript, "Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases," has been formally accepted for publication in PLOS Pathogens."
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"Next, we found that overexpression of HA-OTUD4 interacted with FLAG-USP7 in HEK293T cells and endogenous USP7 also formed a complex with OTUD4 when we induced KSHV lytic reactivation in SLK.iBAC and BCBL-1 cells (Figs 5C and S5G)."
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