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

Max Paget, Cristhian Cadena, Sadeem Ahmad, Hai Tao Wang, Tristan X. Jordan, Ehyun Kim, Beechui Koo, Shawn M. Lyons, Pavel Ivanov, Benjamin tenOever, Xin Mu, Sun Hur

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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 the 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, 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 independently 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.

Original languageEnglish
Pages (from-to)1180-1196.e8
JournalMolecular Cell
Volume83
Issue number7
DOIs
StatePublished - 6 Apr 2023
Externally publishedYes

Keywords

  • ADAR1
  • RIG-I-like receptor
  • antiviral signaling
  • dsRNA
  • immune-mediated apoptosis
  • immunopathology
  • innate immunity
  • integrated stress response
  • molecular condensate
  • stress granule

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