Inhibitors of Deubiquitinating Enzymes Interfere with the SARS-CoV-2 Papain-like Protease and Block Virus Replication In Vitro

Große, Maximilian; Setz, Christian; Rauch, Pia; Auth, Janina; Morokutti-Kurz, Martina; Temchura, Vladimir; Schubert, Ulrich S.

doi:10.3390/v14071404

Cited by 10 publications

(12 citation statements)

References 71 publications

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“…More recently, Setz et al (2017) reported a 90% reduction in the replicative capacity of the human immunodeficiency virus (HIV-1) in lymphoid cells after treatment with PR-619 [ 33 ]. Interestingly, Große et al (2022) found that DUB inhibitors interfere with SARS-CoV2 Papain-like protease enzymatic activity in a dose-dependent manner, thus impairing viral replication [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinating Enzyme Inhibitors Block Chikungunya Virus Replication

López

Calvo

Castellanos

2023

Viruses

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Ubiquitination and deubiquitination processes are widely involved in modulating the function, activity, localization, and stability of multiple cellular proteins regulating almost every aspect of cellular function. Several virus families have been shown to exploit the cellular ubiquitin-conjugating system to achieve a productive infection: enter the cell, promote genome replication, or assemble and release viral progeny. In this study, we analyzed the role of deubiquitinating enzymes (DUBs) during chikungunya virus (CHIKV) infection. HEK293T, Vero-E6, and Huh-7 cells were treated with two DUB inhibitors (PR619 or WP1130). Then, infected cells were evaluated by flow cytometry, and viral progeny was quantified using the plaque assay method. The changes in viral proteins and viral RNA were analyzed using Western blotting and RT-qPCR, respectively. Results indicate that treatment with DUB inhibitors impairs CHIKV replication due to significant protein and viral RNA synthesis deregulation. Therefore, DUB activity may be a pharmacological target for blocking CHIKV infection.

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Section: Discussionmentioning

confidence: 99%

Deubiquitinating Enzyme Inhibitors Block Chikungunya Virus Replication

López

Calvo

Castellanos

2023

Viruses

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“…Interestingly, a proteomics study has identified over 98 ubiquitin ligases and 29 deubiquitinating enzymes that interact with SARS-CoV-2 proteins [ 52 ], underlining the relevance of this post-translational modification not just for the host but also viral proteins. Understanding this interface might lead to the development of novel therapeutic approaches, such as targeting deubiquitinating enzymes to suppress SARS-CoV-2 replication [ 53 ]. These combined findings underline the need for further research to comprehend the intricate network of the ubiquitination and deubiquitination processes.…”

Section: Discussionmentioning

confidence: 99%

MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake

Emslander,

Krey,

Hamad

et al. 2023

Viruses

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Angiotensin-converting enzyme 2 (ACE2) is the central entry receptor for SARS-CoV-2. However, surprisingly little is known about the effects of host regulators on ACE2 localization, expression, and the associated influence on SARS-CoV-2 infection. Here we identify that ACE2 expression levels are regulated by the E3 ligase MDM2 and that MDM2 levels indirectly influence infection with SARS-CoV-2. Genetic depletion of MDM2 elevated ACE2 expression levels, which strongly promoted infection with all SARS-CoV-2 isolates tested. SARS-CoV-2 spike-pseudotyped viruses and the uptake of non-replication-competent virus-like particles showed that MDM2 affects the viral uptake process. MDM2 ubiquitinates Lysine 788 of ACE2 to induce proteasomal degradation, and degradation of this residue led to higher ACE2 expression levels and superior virus particle uptake. Our study illustrates that cellular regulators of ACE2 stability, such as MDM2, play an important role in defining the infection capabilities of SARS-CoV-2.

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“…In addition to manipulating host's ubiquitin regulation system, SARS-CoV-2 can also encode PLpro enzyme, which possesses deubiquitinating and deISGylating activity (Freitas et al, 2020;Klemm et al, 2020;Freitas et al, 2022). Researchers have pointed out that PLpro's capacity to disengage ISG15 from ISGylated modifications may prove to be critical to the virus's replicative cycle (Swaim et al, 2021;Große et al, 2022). Moreover, PLpro's de-ISGylation activity impinges significantly on immune responses.…”

Section: Dub and De-isgylating Activity Of Plpromentioning

confidence: 99%

Role of E3 ubiquitin ligases and deubiquitinating enzymes in SARS-CoV-2 infection

Zhao

Zhang

et al. 2023

Front. Cell. Infect. Microbiol.

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Ever since its emergence in 2019, COVID-19 has rapidly disseminated worldwide, engendering a pervasive pandemic that has profoundly impacted healthcare systems and the socio-economic milieu. A plethora of studies has been conducted targeting its pathogenic virus, SARS-CoV-2, to find ways to combat COVID-19. The ubiquitin-proteasome system (UPS) is widely recognized as a crucial mechanism that regulates human biological activities by maintaining protein homeostasis. Within the UPS, the ubiquitination and deubiquitination, two reversible modifications, of substrate proteins have been extensively studied and implicated in the pathogenesis of SARS-CoV-2. The regulation of E3 ubiquitin ligases and DUBs(Deubiquitinating enzymes), which are key enzymes involved in the two modification processes, determines the fate of substrate proteins. Proteins associated with the pathogenesis of SARS-CoV-2 may be retained, degraded, or even activated, thus affecting the ultimate outcome of the confrontation between SARS-CoV-2 and the host. In other words, the clash between SARS-CoV-2 and the host can be viewed as a battle for dominance over E3 ubiquitin ligases and DUBs, from the standpoint of ubiquitin modification regulation. This review primarily aims to clarify the mechanisms by which the virus utilizes host E3 ubiquitin ligases and DUBs, along with its own viral proteins that have similar enzyme activities, to facilitate invasion, replication, escape, and inflammation. We believe that gaining a better understanding of the role of E3 ubiquitin ligases and DUBs in COVID-19 can offer novel and valuable insights for developing antiviral therapies.

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Inhibitors of Deubiquitinating Enzymes Interfere with the SARS-CoV-2 Papain-like Protease and Block Virus Replication In Vitro

Cited by 10 publications

References 71 publications

Deubiquitinating Enzyme Inhibitors Block Chikungunya Virus Replication

Deubiquitinating Enzyme Inhibitors Block Chikungunya Virus Replication

MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake

Role of E3 ubiquitin ligases and deubiquitinating enzymes in SARS-CoV-2 infection

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