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

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

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