The Role of Viral RNA Degrading Factors in Shutoff of Host Gene Expression

Abstract

Many viruses induce shutoff of host gene expression (host shutoff) as a strategy to take over cellular machinery and evade host immunity. Without host shutoff activity, these viruses generally replicate poorly in vivo, attesting to the importance of this antiviral strategy. In this review, we discuss one particularly advantageous way for viruses to induce host shutoff: triggering widespread host messenger RNA (mRNA) decay. Viruses can trigger increased mRNA destruction either directly, by encoding RNA cleaving or decapping enzymes, or indirectly, by activating cellular RNA degradation pathways. We review what is known about the mechanism of action of several viral RNA degradation factors. We then discuss the consequences of widespread RNA degradation on host gene expression and on the mechanisms of immune evasion, highlighting open questions. Answering these questions is critical to understanding how viral RNA degradation factors regulate host gene expression and how this process helps viruses evade host responses and replicate. Expected final online publication date for the Annual Review of Virology, Volume 9 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The cut site specificity of the influenza A virus endoribonuclease PA-X allows it to discriminate between host and viral mRNAs

“…Studies of viral host shutoff RNases have so far mostly relied on RNA steady-state levels as a proxy for RNA degradation. However, widespread RNA degradation can have multiple downstream effects on other aspects of RNA metabolism (Gaucherand and Gaglia, 2022). Thus, steady-state level analysis may preclude a clear understanding of how these enzymes target RNAs and which RNAs they directly degrade.…”

“…We previously found that PA-X activity is not indiscriminate, as it down-regulates host RNAs synthesized by RNA Polymerase II (RNAPII) but not RNAPI and III 13 . Interestingly, this feature is shared by all characterized viral endoRNases and degradation factors that drive host shutoff 1,14 . In influenza A virus, this specificity may be explained by a connection between PA-X and cellular RNA splicing, which may govern how PA-X reaches its target RNAs 4 .…”

“…Our laboratory previously found that PA-X activity is not indiscriminate, as it down-regulates host RNAs synthesized by RNA Polymerase II (RNAPII) but not RNAPI and III (Khaperskyy et al, 2016). Interestingly, this feature is widely shared by many viral endoRNases and degradation factors that drive host shutoff (Gaglia et al, 2012;Gaucherand and Gaglia, 2022). In influenza A virus, this specificity is likely a result of PA-X using RNA splicing to reach its target RNAs, as PA-X preferentially down-regulates spliced over intronless RNAs (Gaucherand et al, 2019).…”

“…This process, termed host shutoff, is thought to promote viral replication by preventing antiviral responses and redirecting cellular resources to viral processes. Several viruses from divergent families accomplish host shutoff through RNA degradation by endoribonucleases (endoRNases), including the human pathogen influenza A virus, a negative-sense single-stranded RNA virus with a segmented genome [1][2][3] . This convergent evolution highlights the benefit of using endoRNases to induce host shutoff.…”

Modulation of various host cellular machinery during COVID‐19 infection

“…To harbour cellular environment and escape immunological response, viral factors interact with host transcription machinery to alter the expression of immune responsive genes including cytokines, interleukins etc. 8,9 RNA sequencing (RNA-seq) and ribosome profiling of Calu3 cells infected with SARS-CoV2 was performed to determine modulation in gene expression. It was observed that massive production of viral transcripts reduces the percentage of cellular transcripts.…”