Vaccinia Virus as a Master of Host Shutoff Induction: Targeting Processes of the Central Dogma and Beyond

Abstract

The synthesis of host cell proteins is adversely inhibited in many virus infections, whereas viral proteins are efficiently synthesized. This phenomenon leads to the accumulation of viral proteins concurrently with a profound decline in global host protein synthesis, a phenomenon often termed “host shutoff”. To induce host shutoff, a virus may target various steps of gene expression, as well as pre- and post-gene expression processes. During infection, vaccinia virus (VACV), the prototype poxvirus, targets all major processes of the central dogma of genetics, as well as pre-transcription and post-translation steps to hinder host cell protein production. In this article, we review the strategies used by VACV to induce host shutoff in the context of strategies employed by other viruses. We elaborate on how VACV induces host shutoff by targeting host cell DNA synthesis, RNA production and processing, mRNA translation, and protein degradation. We emphasize the topics on VACV’s approaches toward modulating mRNA processing, stability, and translation during infection. Finally, we propose avenues for future investigations, which will facilitate our understanding of poxvirus biology, as well as fundamental cellular gene expression and regulation mechanisms.

Ribosome quality control activity potentiates vaccinia virus protein synthesis during infection

“…As such, viruses may depend on the RQC machinery to rapidly liberate collided ribosomes during viral mRNA translation. Many viruses, including vaccinia virus, antagonize PKR-dependent eIF2α phosphorylation to prevent host shutdown of translation initiation ( Dhungel et al, 2020 ; Meade et al, 2019 ). To examine if ribosome collisions occur at a higher frequency during innate immune or ISR activation when eIF2α phosphorylation is compromised, we utilized mouse embryonic fibroblasts (MEFs) containing either wild-type or S51A mutant eIF2α that cannot be phosphorylated ( Scheuner et al, 2001 ).…”

“…Here, we utilize vaccinia virus to interrogate the interplay between the RQC pathway and viral protein synthesis. Vaccinia virus is known to manipulate host translation shutdown and has a large proteome, allowing for more detailed analysis of how fluctuations in translation capacity affect viral replication ( Dhungel et al, 2020 ). Indeed, previous results have revealed that ZNF598 and uS10 ubiquitylation is needed for optimal vaccinia virus replication ( DiGiuseppe et al, 2018 ).…”

Nanopore sequencing and de novo assembly of a misidentified Camelpox vaccine reveals putative epigenetic modifications and alternate protein signal peptides

“…Much research has gone into the elucidation of nucleic acid modifying proteins of Vaccinia virus, for instance, Vaccinia virus K7R protein has been shown to promote histone methylation associated with heterochromatin formation 15 . Furthermore, it is postulated that epigenetic and genetic mechanisms may also lead to VACV-induced transcription silencing, and VACV infection induces a global degradation of host and viral mRNA 55 . Also, VACV mRNA capping is carried out in three reactions performed by viral enzymes wherein guanine N-7 methylation occurs, and VACV encodes the VP39 protein (J3R) that is known to add a methyl group at the 2′-O position of the first transcribed nucleotide adjacent to the 5′ cap 55 .…”

Why do poxviruses still matter?

“…Research on these poxvirus gene functions will provide molecular tools to decipher aspects of cellular processes, in addition to understanding viral replication strategies. Work in the author's laboratory has recently focused on vaccinia virus factors that interact with host cell protein synthesis and metabolism machinery [51][52][53][54][55][56][57], with the rational that the study of virus interactions with these host housekeeping functions is critical to elucidate the poxvirus replication strategy and the associated fundamental cellular processes.…”