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Review
. 2013 May-Jun;4(3):317-31.
doi: 10.1002/wrna.1162. Epub 2013 Apr 3.

Regulation of stress granules and P-bodies during RNA virus infection

Richard E Lloyd  1
Affiliations
Review

Regulation of stress granules and P-bodies during RNA virus infection

Richard E Lloyd. Wiley Interdiscip Rev RNA. 2013 May-Jun.

Abstract

RNA granules are structures within cells that play major roles in gene expression and homeostasis. Two principle kinds of RNA granules are conserved from yeast to mammals: stress granules (SGs), which contain stalled translation initiation complexes, and processing bodies (P-bodies, PBs), which are enriched with factors involved in RNA turnover. Since RNA granules are associated with silenced transcripts, viruses subvert RNA granule function for replicative advantages. This review, focusing on RNA viruses, discusses mechanisms that manipulate stress granules and P-bodies to promote synthesis of viral proteins. Three main themes have emerged for how viruses manipulate RNA granules; (1) cleavage of key host factors, (2) control of protein kinase R (PKR) activation, and (3) redirecting RNA granule components for new or parallel roles in viral reproduction, at the same time disrupting RNA granules. Viruses utilize one or more of these routes to achieve robust and productive infection.

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Figures

Figure 1
Figure 1
Stress granule assembly and interference by RNA viruses modulating PKR. Virus infection causes stress at multiple levels that reduces host translation through activation of eIF2 kinases, principally PKR, cleavage or inactivation of other initiation factors or other mechanisms. These translation insults convert active polysome mRNPs into stalled translation initiation complex mRNPs containing 40S ribosome subunits, initiation factors and mRNAs. A complex series of events (not depicted) involving nucleation of multiple stress granule proteins such as G3BP1, Tia‐1/TIAR, TDRD3, FUS, TDP43, and HDAC6 plus transport of mRNP complexes on microtubules leads to aggregates of translation initiation complex mRNPs in stress granules. Reovirus and rotavirus can repress SGs, but mechanisms are not known. Note that many viruses control PKR activation; only those discussed in the text are indicated. Also note that stress granule triggers by virus infection may operate at other levels and feed into this scheme.
Figure 2
Figure 2
Virus blockade and co‐opting of stress granule responses. Specific points/proteins where viruses interact with and inhibit or divert the RNA granule assembly pathway are shown. Poliovirus 3Cproteinase cleaves the critical SG‐nucleating protein G3BP1. Several viruses co‐opt G3BP and divert it into novel virus‐induced foci. HCV diverts G3BP1 into replication/assembly complexes together with HCV core, ns5A and ns5B proteins that also associate with lipid droplets. HCVcomplexes also contain many PB components detailed in Figure 3. Flaviviruses divert G3BP1 (with USP10 and caprin1) and TIA1/TIAR to replication complexes by binding the host proteins on virus RNAs. Alphaviruses recruit G3BP1 into viral replication complexes via direct interaction viral protein nsP3. Junin virus (possibly N and G proteins) recruits G3BP1 into replication complexes that also contain translation factors eIF4G and eIF4A.
Figure 3
Figure 3
Pathways of PB disruption by viruses. PBs form via a complex series of events involving remodeling mRNPs by stripping of initiation factors and ribosome subunits, association with GW182, undergoing Pan2/3‐mediated deadenylation,microtubule transport, and association with other RNA decay factors (e.g., Xrn1, Dcp1a, DDX6 (Rck/p54), GW182 and Lsm components of the exosome), and final concentration in P‐bodies. The order of association of factors with mRNPs in PBs is arbitrary. HCV subverts many PB components into novel viral replication/assembly foci with viral core protein that also contain some SG components (e.g., G3BP, Figure 2). Flaviviruses also divert PB factors into replication foci, likely bound with viral RNA through interaction with DDX6(Rck/p54). Poliovirus induces cleavage of Dcp1a and rapid degradation of Xrn1 and Pan3. Rap55 is a critical PB factor that IAV protein NS1 diverts from normal association with PBs. Bunyavirus Junin virus incorporates viral N protein into PBs to interfere with cellular Dcp1a/2 decapping function and facilitate viral cap‐snatching.
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