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.

Keywords: RNP; granule; innate immune response.

Figure 1. Diagram depicting the numerous nucleic acid sensors in the cell

Mammalian cells express various sensors which detect foreign nucleic acids such as DNA, double‐stranded RNA (dsRNA), or modified RNAs. Upon detection of their nucleic acid activator, these sensors initiate innate immune responses which often result in the production of Type I interferon (IFN), pro‐inflammatory cytokines, translational repression, and cell death.

Figure 2. Condensates of nucleic acid sensors with their nucleic acid activators

Several distinct condensates formed by nucleic acid sensors together with their nucleic acid activators have been recently described. Here we summarize the known components and possible functions of each of these condensates.

Figure 3. Model for dsRNA‐induced foci (dRIF) formation

Cytosolic double‐stranded RNA (dsRNA) is bound by multivalent dsRNA‐binding proteins, resulting in the crosslinking of dsRNA–protein assemblies and condensation into dRIF.

Figure 4. Stress granule‐like assemblies during viral infection

(A) In cells lacking RNase L (RNase L(−)), cytosolic double‐stranded RNA (dsRNA) triggers protein kinase R (PKR) activation and phosphorylation of eIF2α, resulting in translational repression and stress granule formation. (B) In cells competent for RNase L (RNase L(+)), cytosolic dsRNA triggers PKR activation and phosphorylation of eIF2α as well as RNase L activation and mRNA degradation, resulting in translational repression and RNase L‐body formation. (C) Novel stress granule‐like paracrine granules were observed to form due to paracrine signaling from infected cells to bystander cells, which correlates with increased antiviral defense.

Figure 5. Possible consequences of condensate formation for signaling

Condensates may enhance or inhibit signaling by condensate components, depending on several factors including enrichment or depletion of activators or repressors of signaling components within the condensate.