Nucleic acid–protein condensates in innate immune signaling

Abstract

The presence of foreign nucleic acids in the cytosol is a marker of infection. Cells have sensors, also known as pattern recognition receptors (PRRs), in the cytosol that detect foreign nucleic acid and initiate an innate immune response. Recent studies have reported the condensation of multiple PRRs including PKR, NLRP6, and cGAS, with their nucleic acid activators into discrete nucleoprotein assemblies. Nucleic acid–protein condensates form due to multivalent interactions and can create high local concentrations of components. The formation of PRR‐containing condensates may alter the magnitude or timing of PRR activation. In addition, unique condensates form following RNase L activation or during paracrine signaling from virally infected cells that may play roles in antiviral defense. These observations suggest that condensate formation may be a conserved mechanism that cells use to regulate activation of the innate immune response and open an avenue for further investigation into the composition and function of these condensates. Here we review the nucleic acid–protein granules that are implicated in the innate immune response, discuss general consequences of condensate formation and signal transduction, as well as what outstanding questions remain.

RNA scaffolds the Golgi ribbon by forming condensates with GM130

“…Its dimerization and RNA binding are required for phase separation into stress granules (Sanders et al, 2020), while deletion of the G3BP dimerization domain suppresses granule formation. Furthermore, stress granules function as part of the antiviral response and various viruses cleave or inhibit G3BP1 dimers to prevent granule assembly allowing the virus to escape the innate immune response (Corbet et al, 2022).…”

Regulation of ribonucleoprotein condensates by RNase L during viral infection

“…In addition to RLBs, several unique cytoplasmic ribonucleoprotein complexes have recently been identified during the antiviral response (reviewed in Corbet, Burke, & Parker, 2022). Paracrine granules (PGs) are SG‐like foci generated from virus‐free supernatant from infected cells and exhibit a unique protein/RNA composition in comparison to SGs (Brocard et al, 2020; Iadevaia et al, 2022).…”

“…(iv) Similar to G3BP1 and other stress‐granule associated RBPs, it is likely that only a small percentage of each PRR localizes to SGs, thus limiting the potential effect of SG association on PRR activation/signaling. (v) Recent studies indicate that dsRNA‐binding PRRs, including PKR, do not localize to SGs (Corbet, Burke, & Parker, 2022; Zappa et al, 2022). (vi) dsRNA does not concentrate in SGs, but instead concentrates in double‐stranded RNA‐induced foci (dRIFs) (Corbet, Burke, & Parker, 2022; Zappa et al, 2022).…”

“…(v) Recent studies indicate that dsRNA‐binding PRRs, including PKR, do not localize to SGs (Corbet, Burke, & Parker, 2022; Zappa et al, 2022). (vi) dsRNA does not concentrate in SGs, but instead concentrates in double‐stranded RNA‐induced foci (dRIFs) (Corbet, Burke, & Parker, 2022; Zappa et al, 2022). Thus, future studies will need to further address these contradictory findings to determine if SGs indeed promote antiviral signaling by concentrating viral dsRNA and PRRs.…”

The notorious R.N.A.

“…Here, RNAs usually interact with proteins, and the composition and subcellular localization contributes to the function of these condensates. The review by Roy Parker's group (Corbet et al , 2022) discusses the role of nucleic acid/protein granules in the context of the innate immune response and also offers more general considerations on condensate formation mechanisms and their functional effects.…”