GSE173953
Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA
Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the innate immune receptors that recognize viral double-stranded RNA (dsRNA) and initiate antiviral immune responses with the potential of triggering systemic inflammation and immunopathology. How the functions of the dsRNA receptors and their downstream effector molecules are coordinately regulated to avoid excessive immune response is poorly understood. We here demonstrate that stress granules (SGs), biomolecular condensates that form in response to various stresses including viral dsRNA, play key roles in regulating dsRNA-triggered immune response. Upon dsRNA stimulation, SGs recruit many innate immune molecules, including RIG-I-like receptors (RLRs), protein kinase R (PKR) and oligoadenylate synthases (OASes), target these molecules and dsRNA for autophagy and limit their functions through sequestration. In the absence of SGs, dsRNA stimulation results in hyperactivation of inflammatory signaling pathways, global translational arrest and bulk RNA degradation, altogether compromising the cellular capacity to restore homeostasis and triggering cell death. In contrast to most dsRNA-induced immune signaling pathways that are hyperactivated in the absence of SGs, a sub-branch of the RLR pathway (IRF3-dependent type I interferon signaling) shows time-dependent changes, where the initial spike in signaling is followed by a significant drop due to increased caspase-dependent negative feedback regulation. This highlights the role of SGs in regulating the delicate balance between the type I interferon pathway and cell death. Altogether, our data suggest that cells utilize SGs as shock absorbers to moderate antiviral innate immune response, thereby allowing cells to guard against its own immune system as well as viruses. Overall design: Two or three biological replicates were analyzed for U2OS and A549 cells both treated/untreated with dsRNA in different genotype and timepoints.