Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

Figures

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  Figure 1. PKR at the crossroads of virus sensing, innate immune signaling, and stress response pathways. Cells evolved several cytosolic sentinels that detect virus infection and initiate defense mechanisms, including innate immune and stress responses. Cytosolic nucleic acid sensors RIG-I, MDA5, and cGAS signal via the mitochondrial adapter protein MAVS and the ER-adapter protein STING, triggering downstream signaling cascades via the IKK complex (IKKγ, IKKα, IKKβ) and IKKε/IKKγ/TBK1. The IKK complex phosphorylates the NF-κB (p50, p65) inhibitor IκB, whose degradation enables the nuclear translocation of NF-κB and transcriptional activation of IFN-β and pro-inflammatory cytokines. TBK1, on the other hand, phosphorylates IRF3/7, whose nuclear translocation mediates the transcriptional activation of IFN-α/β (left side). Cytosolic dsRNA that accumulates during viral replication is sensed by the stress kinase PKR. As a consequence, phosphorylation of eIF2α strongly represses the translation of most cellular mRNAs, while the translation of factors related to the stress response (ATF4, CHOP, and GADD34) or cell survival (XIAP and Bcl-2) is selectively favored (right side). The other…

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  Figure 2. SGs as immune and stress signaling platforms. SGs function as immune and signaling platforms by phase-separating and concentrating regulatory proteins involved in apoptosis induction and other intracellular signaling pathways (A) and IFN signaling. (B). Certain RBPs and cellular mRNAs (e.g., cytokine mRNAs) preferentially localize in SGs (C). Viral components and ITAFs that control viral gene expression are also detected in SGs (D). SG composition is highly stress- and cell type-specific. Notably, many components have been detected in SGs under metabolic or environmental stress conditions, while an investigation in the context of viral infection is still missing. The localization and function of some SG components is dependent on the interaction with specific SG core proteins, indicated in turquoise.

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  Figure 3. SG localization in close proximity to mitochondria. Shown are live-cell microscopy images of HCV-induced dynamic assembly and disassembly of SGs. (A) human hepatocarcinoma Huh7 cells, stably expressing YFP-TIA1 (in yellow) and mTurquoise2-mito [339], a mitochondrial targeting peptide (in cyan), were infected with an HCV-mCherry reporter virus (in red). (B) Cropped section. White arrows indicate examples of SGs that are localized in close proximity to mitochondria (scale bar 10 µM).