The Ubiquitin-Proteasome System Is Necessary for Efficient Replication of Human Astrovirus

Abstract

Astroviruses, members of the family , represent an important cause of human gastroenteritis in the world. The cellular factors required for astrovirus replication have been poorly studied. In this work, we evaluated the relevance of the ubiquitin-proteasome system (UPS) in the replication of Yuc8, a human astrovirus serotype 8 strain. We found that proteasome inhibitors decrease the production of infectious viral progeny at a step in the replication cycle subsequent to virus entry. The inhibition of the proteasome activity decreases viral RNA levels and viral protein synthesis; similarly, the inhibition of ubiquitination by chemical inhibitors or RNAi reduces the production of viral progeny as well as viral protein synthesis. The effect on viral progeny production induced by proteasome inhibitors is not explained by a reduction in the pool of monoubiquitin or the induction of early apoptosis or autophagy. Our observations are consistent with the need of the proteolytic activity of the UPS for the efficient replication of the virus and suggest that UPS is necessary for the production of genomic and subgenomic RNA but not for antigenomic RNA. Astroviruses are a major cause of gastroenteritis in young humans and animals and recently it has been associated to fatal encephalitis in humans. The role of ubiquitin proteasome system in the replication of these viruses has not been studied before. In this work, we present evidence that supports that the proteolytic activity of proteasome is necessary for efficient viral progeny production, and that this proteolytic system is required for the accumulation of both, the genomic and subgenomic viral RNAs.

Pleiotropic roles of the ubiquitin-proteasome system during viral propagation

“…The UPS can be manipulated by many viruses to facilitate viral replication, but the proteasome inhibitor MG132 can inhibit viral replication [20,46,47]. For example, the replication of some viruses such as human astrovirus [47], vaccinia virus [48], tombusvirus [49], hepatitis E virus [50,51], porcine circovirus type 2 [52], and Ebola virus [53] are regulated by the UPS, and recent studies revealed that the UPS is necessary for the efficient replication of African swine fever virus and human astrovirus [20,47]. Among these viruses, some encode specific proteins that modify the host Ub machinery.…”

Ubiquitin–Proteasome System Is Required for Efficient Replication of Singapore Grouper Iridovirus

“…The UPS can be exploited by different mammalian viruses during their life cycles, including during entry, assembly and release ( Harty et al, 2001 ; Ott et al, 2002 ; Delboy et al, 2008 ; Kaspari et al, 2008 ; Tran et al, 2010 ; Widjaja et al, 2010 ; Casorla-Pérez et al, 2017 ). However, the potential roles of the UPS in fish viral infections remain largely uncertain ( Huang et al, 2017 ).…”

“…The ubiquitin-proteasome system (UPS) is the major intracellular protein degradation pathway and plays crucial roles in a variety of fundamental cellular processes, including regulation of gene transcription, cell cycle progression, autophagy, development and differentiation, and modulation of the immune and inflammatory responses ( Glickman and Ciechanover, 2002 ; Wertz and Dixit, 2008 ; Zhao and Goldberg, 2016 ). There is increasing evidence that the UPS is required for viral infection by affecting viral entry, gene transcription, assembly, release and immune evasion ( Banks et al, 2003 ; Wang et al, 2016 ; Casorla-Pérez et al, 2017 ). To the best of our knowledge, DNA viruses, as well as RNA viruses from different hosts, including mammals, insects, and plants, exploit the UPS system at various stages of the viral life cycle ( Camborde et al, 2010 ; Contin et al, 2011 ; Katsuma et al, 2011 ; Greene et al, 2012 ; Wang et al, 2016 ).…”

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

“…The ubiquitin-proteasome system (UPS) plays important roles in the degradation of proteins, the immune response, and signal transduction (Casorla-Perez et al, 2017). 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).…”