Fine-tuning a blunt tool: Regulation of viral host shutoff RNases

Abstract

The evolutionary arms race between host and pathogen has resulted in the ability of many human viruses to alter the host gene expression profile during infection, in order to redirect cellular resources towards viral gene expression and inhibit cell-intrinsic host immune responses. In particular, multiple viruses globally reduce host gene expression in a process termed "host shutoff." Multiple mechanisms of host shutoff exist, including translational and transcriptional shutoff, but several viruses carry out host shutoff by encoding ribonucleases (RNases) that degrade host messenger RNAs (mRNAs). Viral host shutoff RNases include the influenza A virus polymerase acidic-X (PA-X) [1], the herpes simplex viruses (HSV-1 and -2) virion host shutoff protein (vhs) [2], and the Kaposi's sarcoma-associated herpesvirus (KSHV) shutoff and exonuclease (SOX) protein [3] and its homologs, muSOX from murine gammaherpesvirus 68 (MHV68) [4] and BGLF5 from Epstein-Barr virus (EBV) [5]. These RNases contribute to efficient formation of virions and/or reduction of innate immune signaling [6][7][8]. For example, in the absence of EBV BGLF5, the virus produces fewer mature capsids, many of which remain trapped in the nucleus [7]. Vhs-deficient HSV replicates well in many common tissue culture models [9] but shows replication defects in relevant cell types, such as cerebellar granule neurons [8]. Moreover, in mice, viruses lacking detectable host shutoff activity replicate to lower viral titers in neuronal tissue [9], indicating a restriction of viral replication probably related to host immune responses. Influenza A virus PA-X also limits host antiviral and proinflammatory responses in several animal models [1,10,11] but has minimal effect on viral replication both in vivo and in cell culture [1,11,12]. Although host shutoff RNases are important for successful viral infection, their activity presents an interesting problem for the viruses that encode them. Unregulated RNase activity could degrade viral RNAs or host mRNAs encoding proteins that the virus needs. Moreover, drastic depletion of the mRNA pool by the virus could trigger antiviral host stress responses and cell death. It is thus unsurprising that evidence is now emerging that viruses posttranslationally regulate the activity of their host shutoff RNases through a variety of mechanisms, reviewed herein (Fig 1), to finetune host gene regulation without inhibiting viral replication. Selection of targeted and protected RNAs and protein/protein interactionsAll host shutoff RNases cause global decreases in host mRNA abundance, revealed by transcriptome-wide studies [13][14][15], and display a preference for mRNAs while sparing housekeeping noncoding RNAs (ncRNAs) [12,16,17]. However, host shutoff RNases are less PLOS PATHOGENS PLOS Pathogens | https://doi.

Remodeling of the Ribosomal Quality Control and Protein Translation by a Viral Ubiquitin Deconjugase

“…During productive EBV infection, more than seventy different viral proteins reprogram the cellular environment to allow virus replication and provide the building blocks of new virus particles (Kenney, 2007). The known viral mechanisms for interfering with translation often involve the expression of RNA-binding proteins that mimic or hijack components of the translation machinery (Daly et al, 2020).…”

“…During productive EBV infection, more than seventy different viral proteins reprogram the cellular environment to allow virus replication and provide the building blocks of new virus particles (Kenney, 2007). The known viral mechanisms for interfering with translation often involve the expression of RNA-binding proteins that mimic or hijack components of the translation machinery (Daly et al, 2020). Here, we have discovered a new strategy by which EBV reprograms translation by harnessing the activity of the ubiquitin deconjugase encoded in the N-terminal domain of the large tegument protein BPLF1 (vDUB) to inhibit the RQC and ER-RQC, trigger a GCN2 kinase-dependent integrated stress response, and promote the readthrough of stall- inducing viral mRNAs.…”

Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection

“…This global RNA decay is orchestrated within the cytoplasm by a single viral endoribonuclease. This strategy is surprisingly well conserved among related alpha-and gammaherpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) ORF37 (SOX), Herpes Simplex virus-1 (HSV-1) vhs, Epstein-Barr Virus (EBV) BGLF5, and the Murine Herpesvirus 68 (MHV68) muSOX [47][48][49]. There are also several RNA viruses that have evolved the same host-shutoff strategy, including several human coronaviruses and influenza A virus (IAV) [50][51][52].…”

Modulation of mRNA 3′-End Processing and Transcription Termination in Virus-Infected Cells

“…Diverse mechanisms underlie these effects on host cells, including suppression of transcription through interaction of viral proteins with transcription factors and promoters, inhibition of Pol II elongation, and degradation of Pol II through ubiquitination (28)(29)(30)(31). Viral infection also interferes with mRNA processing and stability through its effects on splicing, 5´capping, and nuclear export of cellular mRNAs as well as induction of mRNA degradation (32)(33)(34)(35)(36)(37). Many mechanisms for selectively expressing viral over host genes alter the population of mRNAs available for translation rather than destroying or inhibiting the translational machinery, thereby enabling the virus to continue to utilize host ribosomes to translate its own mRNAs (26).…”