The ubiquitin-proteasome system is required for African swine fever replication

Abstract

Several viruses manipulate the ubiquitin-proteasome system (UPS) to initiate a productive infection. Determined viral proteins are able to change the host’s ubiquitin machinery and some viruses even encode their own ubiquitinating or deubiquitinating enzymes. African swine fever virus (ASFV) encodes a gene homologous to the E2 ubiquitin conjugating (UBC) enzyme. The viral ubiquitin-conjugating enzyme (UBCv1) is expressed throughout ASFV infection and accumulates at late times post infection. UBCv is also present in the viral particle suggesting that the ubiquitin-proteasome pathway could play an important role at early ASFV infection. We determined that inhibition of the final stage of the ubiquitin-proteasome pathway blocked a post-internalization step in ASFV replication in Vero cells. Under proteasome inhibition, ASF viral genome replication, late gene expression and viral production were severely reduced. Also, ASFV enhanced proteasome activity at late times and the accumulation of polyubiquitinated proteins surrounding viral factories. Core-associated and/or viral proteins involved in DNA replication may be targets for the ubiquitin-proteasome pathway that could possibly assist virus uncoating at final core breakdown and viral DNA release. At later steps, polyubiquitinated proteins at viral factories could exert regulatory roles in cell signaling.

Pleiotropic roles of the ubiquitin-proteasome system during viral propagation

“…The UPS is a doubleedged sword in viral pathogenesis; host cells employ the UPS to degrade viral proteins to limit viral infection, but viruses can manipulate the UPS machinery to degrade cellular restriction factors, thereby facilitating viral propagation. To date, many viruses have been reported to reprogram the UPS to satisfy their needs, and the UPS can function in different stages of the viral life cycle, including viral capsid uncoating [35,36], viral replication [37][38][39], gene transcription [40,41], viral envelopment [42], and viral progeny release [43,44]. Furthermore, the UPS was reported to play an important role during various stages of the coronavirus (CoV) infection cycle [45], and it could potentially be developed as a drug target to modulate the impact of CoV infection in the future.…”

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.…”

“…Generally, it is a double-edged sword in viral pathogenesis; host cells employ the UPS to degrade viral proteins to limit viral infection, meanwhile, viruses can manipulate the UPS machinery to degrade cellular restriction factors in order to facilitate viral propagation. 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.…”

ICTV Virus Taxonomy Profile: Asfarviridae

“…After capsid degradation and membrane fusion, viral cores exit endosomes. The ubiquitin-proteasome system is involved in final degradation of the viral cores to set free the viral DNA in order to start replication [4]. Virus DNA replication and assembly take place in perinuclear factory areas, to which the virus is transported in association with the microtubular motor light-chain dynein.…”