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.
Highlights
Introduction to Host ShutoffViruses are obligatory intracellular parasites that only replicate in host cells
These results suggest that vaccinia virus (VACV) messenger RNAs (mRNAs) translation is less dependent on poly(A) binding protein (PABP), which is in agreement with the finding that PABP1 is localized outside of viral factories, where viral mRNA
VACV employs wide-ranging strategies that target the key processes of gene expression, as well as pre- and post-gene expression processes: inhibiting host DNA synthesis and mRNA transcription, interfering with host mRNA processing and maturation, hijacking host translation machinery to preferentially synthesize viral proteins, and systematically promoting host protein degradation
Summary
Viruses are obligatory intracellular parasites that only replicate in host cells. viruses encode various numbers of genes to perform replication, they rely on cellular translation machinery for protein synthesis. Competition exists between viruses and their hosts to utilize the limited amount of cellular translation machinery. This situation instigates many viruses to induce a rapid and profound decline in global host protein synthesis while continuously synthesizing the viral proteins, a phenomenon often termed “host shutoff”. Studies on virus-induced host shutoff to date have indicated that some viruses allocate proteins to inhibit DNA synthesis and transcription; more often, many viruses encode an arsenal of proteins targeting mRNA processing and translation. In addition to encoding multiple classes of immunomodulatory proteins, the abolishment of the host cells’ ability to produce proteins, including those involved in an antiviral response, provides viruses with a powerful strategy to counteract an immune response. Numerous questions remain unanswered regarding understanding VACV-induced host shutoff, which provides many opportunities to elucidate mechanisms of poxvirus replication and fundamental cellular biology mechanisms
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