Abstract
Stress granules (SGs) are highly dynamic cytoplasmic foci that form in response to activation of the integrated stress response (ISR) that results in eIF2α phosphorylation and global translation shutdown. Stress granules, which are largely nucleated by G3BP1, serve as hubs for mRNA triage, but there is mounting evidence that they also perform cell signaling functions that are vital to cell survival, particularly during viral infection. We previously showed that SG formation leads to NFκB activation and JNK signaling and that this association may be due in part to G3BP1-dependent recruitment of PKR to SGs. Others have reported close associations between G3BP1 and various innate immune PRRs of the type 1 interferon signaling system, including RIG-I. We also reported SG assembly dynamics is dependent on the arginine-methylation status of G3BP1. Another protein that rapidly localizes to SGs, TDRD3, is a methyl reader protein that performs transcriptional activation and adaptor functions within the nucleus, but neither the mechanism nor its function in SGs is clear. Here, we present evidence that TDRD3 localizes to SGs partly based upon methylation potential of G3BP1. We also characterize granules that TDRD3 forms during overexpression and show that these granules can form in the absence of G3BP but also contain translation components found in canonical SGs. We also show for the first time that SGs recruit additional interferon effectors IRF3, IRF7, TBK1, and Sting, and provide evidence that TDRD3 may play a role in recruitment of these factors. We also present evidence that TDRD3 is a novel antiviral protein that is cleaved by enteroviral 2A proteinase. G3BP1 and TDRD3 knockdown in cells results in altered transcriptional regulation of numerous IFN effectors in complex modulatory patterns that are distinctive for G3BP1 and TDRD3. Overall, we describe a novel role of TDRD3 in innate immunity in which G3BP1 and TDRD3 may coordinate to play important roles in regulation of innate antiviral defenses.
Highlights
Stress granules (SGs) are messenger ribonucleoprotein condensates, consisting largely of stalled translation initiation complexes of mRNAs which form in response to various homeostatic insults [1,2]
When cells are exposed to environmental stresses, such as oxidative stress and viral infection, it induces a cellular response leading to the formation of Stress Granules (SGs) composed of stalled translation initiation complexes (RNA-binding proteins and mRNA) and many other cellular proteins
We show that a methyl reader protein, TDRD3, localizes to SGs partly based on the methylation potential of G3BP1, and may play a role in the recruitment of innate immune factors to SGs
Summary
Stress granules (SGs) are messenger ribonucleoprotein (mRNP) condensates, consisting largely of stalled translation initiation complexes of mRNAs which form in response to various homeostatic insults [1,2]. While there are four known eIF2α kinases (GCN2, PERK, HRI and PKR) that are activated during different types of environmental stresses, their downstream signaling converges upon stress granules [1]. This integration of signaling via divergent kinases resulting in a concerted response is referred to as the integrated stress response (ISR) [8]. In addition to PKR activation through SG recruitment, G3BP1 by itself has been shown to promote DNA binding and activation of the DNA sensor cGAS, leading to the subsequent activation of type 1 interferon signaling [12]. G3BP1 binds HCV viral dsRNA leading to the upregulation of interferon beta expression. This was mediated by G3BP1’s arginine-rich RGG domain [14]–a disordered region at the Cterminus of G3BP1 that is a site for arginine methylation [15]
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