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)- 1? and IL-18.Despite the ability ofNLRP3to 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 regulatorofNLRP3inflammasometocanonicalandviraltriggers.InthisR01renewal,weproposetoidentify the molecular and cellular mechanisms of DDX3X-mediated NLPR3 inflammasome activation and its modulationbystresssignalsduringinflammationandviralinfections.Understandingthecross-talkbetween cellular stress response molecules and innate immune signaling will lead to novel therapeutic targets for inflammatoryandinfectiousdiseases.
STATEMENT Stressgranulesandtheircomponentshavebeenimplicatedinvariousbiologicalprocessesrelatedtohuman healthincludingregulationofinfectious,inflammatory,andneurodegenerativediseases.However,thereisa major gap in the field regarding the intersection between innate immune response and stress response in multiplehumandiseases,includingviralinfections.Ourproposalwilluncoverthemechanismsgoverningthe cross-talkbetweenstress responseandhost innate immune pathwaysthatdictate protectiveorpathogenic hostresponsewhichcouldbetargetedtherapeutically.
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