Stress granules: regulators or by‐products?

Abstract

Cells have to deal with conditions that can cause damage to biomolecules and eventually cell death. To protect against these adverse conditions and promote recovery, cells undergo dramatic changes upon exposure to stress. This involves activation of signaling pathways, cell cycle arrest, translational reprogramming, and reorganization of the cytoplasm. Notably, many stress conditions cause a global inhibition of mRNA translation accompanied by the formation of cytoplasmic condensates called stress granules (SGs), which sequester mRNA together with RNA‐binding proteins, translation initiation factors, and other components. SGs are highly conserved in eukaryotes, suggesting that they perform an important function during the stress response. Over the years, many different roles have been assigned to SGs, including translational control, mRNA storage, regulation of mRNA decay, antiviral innate immune response, and modulation of signaling pathways. Most of our understanding, however, has been deduced from correlative data based upon the composition of SGs and only recently have technological innovations allowed hypotheses for SG function to be directly tested. Here, we discuss these challenges and explore the evidence related to the function of SGs.

Novel stress granule-like structures are induced via a paracrine mechanism during viral infection

“…A well-known antiviral response is the induction of type I interferons (IFNs). During viral replication, double-stranded RNA replication intermediates can be recognized by cytoplasmic sensors such as RIG-I-like receptors (RLRs) or the eIF2α kinase PKR (EIF2AK2) to amplify the IFN response and create an antiviral state ( Eiermann et al, 2020 ; Mateju and Chao, 2021 ). Multiple IFN signalling molecules, including PKR, MDA5 (also known as IFIH1), RIG-I (also known as DDX58) and TRAF2, can be recruited to SGs, and this localization has been suggested to regulate their activity ( Eiermann et al, 2020 ; Mateju and Chao, 2021 ).…”

“…During viral replication, double-stranded RNA replication intermediates can be recognized by cytoplasmic sensors such as RIG-I-like receptors (RLRs) or the eIF2α kinase PKR (EIF2AK2) to amplify the IFN response and create an antiviral state ( Eiermann et al, 2020 ; Mateju and Chao, 2021 ). Multiple IFN signalling molecules, including PKR, MDA5 (also known as IFIH1), RIG-I (also known as DDX58) and TRAF2, can be recruited to SGs, and this localization has been suggested to regulate their activity ( Eiermann et al, 2020 ; Mateju and Chao, 2021 ). Furthermore, SGs or specific antiviral SGs (avSGs) have been proposed to play a role in antiviral signalling, as key signalling proteins including MDA5 and PKR are known to localise to SGs and SG formation is involved in PKR activation ( Eiermann et al, 2020 ; Mateju and Chao, 2021 ).…”

“…Multiple IFN signalling molecules, including PKR, MDA5 (also known as IFIH1), RIG-I (also known as DDX58) and TRAF2, can be recruited to SGs, and this localization has been suggested to regulate their activity ( Eiermann et al, 2020 ; Mateju and Chao, 2021 ). Furthermore, SGs or specific antiviral SGs (avSGs) have been proposed to play a role in antiviral signalling, as key signalling proteins including MDA5 and PKR are known to localise to SGs and SG formation is involved in PKR activation ( Eiermann et al, 2020 ; Mateju and Chao, 2021 ). Because of this proposed role in antiviral signalling and impact on cellular protein synthesis which they rely on, many viruses have evolved strategies to antagonize or exploit SGs, for example by cleaving or repurposing SG-nucleating proteins during infection or impairing the eIF2α sensing pathway ( Gaete-Argel et al, 2019 ).…”

Paracrine granules are cytoplasmic RNP granules distinct from stress granules that assemble in response to viral infection

“…A well-known antiviral response is the induction of type I interferons (IFNs). During viral replication, double-stranded RNA replication intermediates can be recognized by cytoplasmic sensors such as RIG-I-like receptors (RLRs) or the eIF2α kinase PKR to amplify the IFN response and create an antiviral state (Eiermann et al, 2020;Mateju and Chao, 2021).…”

“…Multiple IFN signalling molecules, including PKR, MDA5, RIG-I, PKR, and TRAF2, can be recruited to SGs, and this localization has been suggested to regulate their activity (Eiermann et al, 2020;Mateju and Chao, 2021). Furthermore, SGs or specific antiviral SGs (avSG) have been proposed to play a role in antiviral signalling as key signalling proteins including MDA5 and PKR are known to localise to SGs and SG formation is involved in PKR activation (Eiermann et al, 2020;Mateju and Chao, 2021).…”