Stress granules are shock absorbers that prevent excessive innate immune responses to dsRNA

Summary Proper defense against microbial infection depends on the controlled activation of the immune system. This is particularly important for the RIG-I-like receptors (RLRs), which recognize viral dsRNA and initiate antiviral innate immune responses with the potential of triggering systemic inflammation and immunopathology. Here we show that stress granules (SGs), molecular condensates that form in response to various stresses including viral dsRNA, play key roles in controlled activation of RLR signaling. Without the SG nucleators G3BP1/2 and UBAP2L, dsRNA triggers excessive inflammation and immune-mediated apoptosis. In addition to exogenous dsRNA, we find that host-derived dsRNA generated in response to ADAR1 deficiency is also controlled by SG biology. Intriguingly, SGs can function beyond immune control by suppressing viral replication independent of the RLR pathway. These observations thus highlight the multi-functional nature of SGs as cellular “shock absorbers” that converge on protecting cell homeostasis–by dampening both toxic immune response and viral replication.