The Ubiquitin-Proteasome System Plays an Important Role during Various Stages of the Coronavirus Infection Cycle

Abstract

The ubiquitin-proteasome system (UPS) is a key player in regulating the intracellular sorting and degradation of proteins. In this study we investigated the role of the UPS in different steps of the coronavirus (CoV) infection cycle. Inhibition of the proteasome by different chemical compounds (i.e., MG132, epoxomicin, and Velcade) appeared to not only impair entry but also RNA synthesis and subsequent protein expression of different CoVs (i.e., mouse hepatitis virus [MHV], feline infectious peritonitis virus, and severe acute respiratory syndrome CoV). MHV assembly and release were, however, not appreciably affected by these compounds. The inhibitory effect on CoV protein expression did not appear to result from a general inhibition of translation due to induction of a cellular stress response by the inhibitors. Stress-induced phosphorylation of eukaryotic translation initiation factor 2␣ (eIF2␣) generally results in impaired initiation of protein synthesis, but the sensitivity of MHV infection to proteasome inhibitors was unchanged in cells lacking a phosphorylatable eIF2␣. MHV infection was affected not only by inhibition of the proteasome but also by interfering with protein ubiquitination. Viral protein expression was reduced in cells expressing a temperature-sensitive ubiquitin-activating enzyme E1 at the restrictive temperature, as well as in cells in which ubiquitin was depleted by using small interfering RNAs. Under these conditions, the susceptibility of the cells to virus infection was, however, not affected, excluding an important role of ubiquitination in virus entry. Our observations reveal an important role of the UPS in multiple steps of the CoV infection cycle and identify the UPS as a potential drug target to modulate the impact of CoV infection.

Role of the ubiquitin-proteasome system in Bombyx mori nucleopolyhedrovirus infection

“…Using proteasome inhibitors such as MG-132, viruses belonging to several different families have been shown to utilize or modulate this system to their advantage during their infection cycles (Raaben et al, 2010;Satheshkumar et al, 2009;Teale et al, 2009). In this study, we examined whether the ubiquitin-proteasome system is required for efficient BmNPV infection.…”

The ubiquitin-proteasome system is necessary for the replication of duck Tembusu virus

“…The UPS plays a crucial role in the degradation of intracellular proteins and regulates the cellular signal transduction [13]. Many viruses have exploited the UPS system to their own advantage [19,20,27,29]. However, the potential roles of the UPS in duck TMUV infections remain largely uncertain.…”

“…To date, many viruses have been reported to utilize the UPS to satisfy their needs, and the UPS machinery can work in different stages of the viral life cycle, such as viral capsid uncoating [17,18], viral replication [19][20][21], gene transcription [22,23], viral envelopment [24], and viral progeny release [25,26]. Furthermore, in Coronavirus (CoV), the UPS was reported to play an important role during various stages of infection cycle [27], and it could potentially be developed as a drug target to modulate the impact of CoV infection in future.…”

Seneca Valley Virus 3C protease negatively regulates the type I interferon pathway by acting as a viral deubiquitinase

“…The UPS is a double-edged sword in viral pathogenesis: the UPS is necessary for many viruses replication by maintaining the proper functions of viral proteins (Barrado-Gil et al, 2017;Luo, 2016;Wang et al, 2016); the UPS can constitute host immune system to reduce viral replication (Luo, 2016). For example, the UPS was essential for coronavirus replication (Raaben et al, 2010), whereas coronavirus papain-like proteases can act as DUBs that block type I IFN production (Clementz et al, 2010). Proteasome inhibitors MG132 can inhibit the UPS.…”