Stress Granules

G3BP and Stress Granules in Viral infection

Stress granules (SGs) are dynamic sites of mRNA storage, which are formed in the cytoplasm of cells under many types of environmental stress. The sequestration of mRNAs into these translationally silent cytoplasmic foci contributes to the rapid redirection of translation from housekeeping proteins to heat-shock proteins and other stress response factors. In 2005, we showed that SFV infection induces the very transient appearance of SGs in the cytoplasm (McInerney et al., 2005). The timing if this corelated with the change in profile of protein production from host  to viral. In infected cells, SGs are induced by the protein kinase R (PKR)-dependent phosphorylation of eukaryotic translation initiation factor 2 but the cause of SG disassembly was not clear at that time. Since publication of that paper, transient SG formation has been revealed to be a common feature of many diverse viral infections.

We have recently shown that SG disruption by SFV is mediated by the recruitment of the SG protein G3BP into viral replication complexes (Panas et al., 2012). We showed that this recruitment is dependent on two FGDF motifs in the extreme C terminal end of nsP3 (Panas et al., 2015).

Publications on this topic

Thomas Kruse, Caroline Benz, Dimitriya H. Garvanska, Richard Lindqvist, Filip Mihalic, Fabian Coscia, Ravi Teja, Inturi, Ahmed Sayadi, Leandro Simonetti, Emma Nilsson, Muhammad Ali, Johanna Kliche, Ainhoa Moliner Morro, Andreas Mund, Eva Andersson, Gerald McInerney, Matthias Mann, Per Jemth, Norman E Davey, Anna K Överby, Jakob Nilsson, Ylva Ivarsson (2021) Large scale discovery of coronavirus-host factor protein interaction motifs reveals SARS-CoV-2 specific mechanisms and vulnerabilities. Nature Communications,12(1):6761.

Hendrik Reuper, Benjamin Götte, Lucy Williams, Timothy J.C. Tan, Gerald McInerney, Marc D. Panas and Björn Krenz (2021) Arabidopsis thaliana G3BP ortholog rescues mammalian stress granule phenotype across kingdoms. International Journal of Molecular Sciences 22(12):6287.

Götte B*, Utt A*, Fragkoudis R, Merits A# and McInerney G# (2020). Sensitivity of alphaviruses to G3BP deletion correlates with efficiency of replicase polyprotein processing. J Virol, 94:e01681-19.
*, # equal contribution

Liu L, Weiss E, Panas MD, Götte B, Sellberg S, Thaa B and McInerney GM (2019). RNA Processing Bodies are Disassembled during Old World Alphavirus Infection. J Gen Virol, 100:1375-138.

Götte B, Panas M, Hellström K, Liu L, Samreen B, Larson O, Ahola T, McInerney G (2019). Separate domains of G3BP promote efficient clustering of alphavirus replication complexes and recruitment of the translation initiation machinery. PLoS Pathogens, 15(6):e1007842.

Schulte T, Liu L, Panas MD, Thaa, B, Dickson N, Götte B, Achour A and McInerney GM. (2016) Combined structural, biochemical and cellular evidence demonstrates that both FGDF motifs in alphavirus nsP3 are required for efficient replication. Open Biology, doi: 10.1098/rsob.160078.

Kedersha N, Panas MD, Achorn CA, Lyons S, Tisdale S, Hickman T, Thomas M, Lieberman J, McInerney GM, Ivanov P, Anderson P. (2016) G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits. J Cell Biol. 212:845-60.

McInerney, G.M. (2015)    FGDF Motif Regulation of Stress Granule Formation. DNA Cell Biol. 34:557–5604.

Panas, M.D., Kedersha, N. and McInerney, G.M. (2015)  Methods for the characterization of stress granules in virus infected cells. Methods.         doi:10.1016/j.ymeth.2015.04.009.

Panas, M.D., Schulte, T., Thaa, B., Sandalova, T., Achour, A., Kedersha, N.L. and McInerney G.M. (2015). Viral and cellular proteins containing FGDF motifs bind G3BP to block stress granule formation. PLoS Pathogens,11(2):e1004659.

Panas, M.D., Ahola, T. and McInerney, G.M. (2014). The C-terminal repeat domains of nsP3 from the Old World alphaviruses bind directly to G3BP. J Virol, 88:5888-5893.

Panas, M.D., Varjak, M., Lulla, A., Eng, K.E., Merits, M., Karlsson Hedestam, G.B.  and McInerney, G.M. (2012). Sequestration of G3BP coupled with efficient translation inhibits stress granules in Semliki Forest virus infection. Mol Biol Cell, 23:4701-4712.

McInerney, G.M., Kedersha, N.L., Kaufman, R.J., Anderson, P. and Liljeström P. (2005). Importance of eIF2alpha phosphorylation and stress granule assembly in alphavirus translation regulation. Mol Biol Cell 16:3753–3763.