Regulation of stress granules in virus systems

Abstract

Virus infection initiates a number of cellular stress responses that modulate gene regulation and compartmentalization of RNA. Viruses must control host gene expression and the localization of viral RNAs to be successful parasites. RNA granules such as stress granules and processing bodies (PBs) contain translationally silenced messenger ribonucleoproteins (mRNPs) and serve as extensions of translation regulation in cells, storing transiently repressed mRNAs. New reports show a growing number of virus families modulate RNA granule function to maximize replication efficiency. This review summarizes recent advances in understanding the relationship between viruses and mRNA stress granules in animal cells and will discuss important questions that remain in this emerging field.

Figure 1

Stress granules (SGs) are intermediate compartments in mRNA metabolism. Inhibition of translation initiation leads to the disassembly of polysomes and the formation of stalled 48S initiation complexes. These messenger ribonucleoprotein (mRNP) complexes are recognized via an unknown mechanism and are remodeled, marking them for inclusion in SGs despite continued association with pro-translation initiation factors. SG components such as RasGAP SH3-domain binding protein 1 (G3BP1), Fragile X mental retardation protein (FMRP) and others are post-translationally modified, and small dispersed aggregates of remodeled mRNP complexes are transported by microtubule-associated motor proteins into larger SGs. The brackets around this central step indicate that it is not currently known which process is initially undertaken. SGs are thought to be sites of storage of stabilized mRNA, although it is known that mRNA can be released for translation or transported to processing bodies (PBs) for active decay by an unknown mechanism. Multiple virus systems (in red) have been found to interfere with the process of SG and PB formation and the points of interaction with the process are indicated. Stress granules also dock with PBs where mRNP modification and cargo exchange takes place. Initiation factors are lost except eukaryotic translation initiation factor (eIF4E) and deadenylase complexes (Pan2/3, Caf1/Ccr4) decapping complexes (Dcp1a/2) and exonucleases (Xrn1) become associated. Some viruses inhibit PB formation as indicated and poliovirus (PV) antagonizes specific PB components , , .

Figure 2

Inhibition of stress granule (SG) formation by several viral systems has been characterized in more detail and two types of mechanisms are illustrated: cleavage or sequestration of SG components. Cleavage of RasGAP SH3-domain binding protein 1 (G3BP1) by poliovirus (PV) 3C proteinase inhibits the inclusion of translation initiation factors, mRNA binding proteins and mRNA in SGs without modulating the ability of T-cell restricted intracellular antigen 1 (TIA-1) and TIA-1-related protein (TIAR) to aggregate. Human T-cell leukemia virus type-1 (HTLV-1) Tax protein interacts with histone deacetylase 6 (HDAC6) to inhibit SG formation, whereas the HIV Gag protein binds to Staufen1. The 3′ stem loop present in flavivirus negative sense RNA binds and sequesters TIA-1 and TIAR, leading to the inhibition of SGs. Through unknown mechanisms, cricket paralysis virus (CrPV) prevents accumulation of Drosophila homologs of TIA1 (Rox8) and G3BP (Rin) in SGs.