Innate immune signaling and stress response

ABSTRACT Membraneless compartments play a vital role in maintaining cellular and organismal homeostasis by modulating cell survival and cell death. Stress granules, and inflammasome-­induced specks are membraneless compartments that provide contrasting cell fate choices to the cells – survival or pyroptosis (programmed cell death) during physiological or virus induced cellular stress. NLRP3, a global sensor of pathogen–associated molecular patterns (PAMPs) and danger–associated molecular patterns (DAMPs), senses cellular perturbations in the cytosol to trigger the assembly of a large caspase-­1-­activating protein complex termed the NLRP3 inflammasome. Autoproteolytic maturation of caspase-­1 due to NLRP3 inflammasome activation leads to pyroptosis, and maturation of pro-­inflammatory cytokines interleukin (IL)-­ 1β and IL-­18. Despite the ability of NLRP3 to respond to diverse cues of cellular or virus induced stress, mechanisms controlling the cross-­talk between inflammasomes and stress granules remain elusive. In our quest to study this cross-­talk, we have identified DDX3X, a stress granule component, as an upstream regulator of NLRP3 inflammasome to canonical and viral triggers. In this R01 renewal, we propose to identify the molecular and cellular mechanisms of DDX3X-­mediated NLPR3 inflammasome activation and its modulation by stress signals during inflammation and viral infections. Understanding the cross-­talk between cellular stress response molecules and innate immune signaling will lead to novel therapeutic targets for inflammatory and infectious diseases.