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)- 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.

Public Health Relevance

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI124346-06
Application #
9901240
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Liu, Qian
Project Start
2016-03-15
Project End
2026-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
6
Fiscal Year
2021
Total Cost
Indirect Cost

  Institution

Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105

  Publications

Zhu, Qifan; Man, Si Ming; Karki, Rajendra et al. (2018) Detrimental Type I Interferon Signaling Dominates Protective AIM2 Inflammasome Responses during Francisella novicida Infection. Cell Rep 22:3168-3174
Balakrishnan, Arjun; Karki, Rajendra; Berwin, Brent et al. (2018) Guanylate binding proteins facilitate caspase-11-dependent pyroptosis in response to type 3 secretion system-negative Pseudomonas aeruginosa. Cell Death Discov 4:3
Tartey, Sarang; Gurung, Prajwal; Dasari, Tejasvi Krishna et al. (2018) ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis. J Clin Invest 128:2042-2047
Karki, Rajendra; Lee, Ein; Place, David et al. (2018) IRF8 Regulates Transcription of Naips for NLRC4 Inflammasome Activation. Cell 173:920-933.e13
Malireddi, R K Subbarao; Gurung, Prajwal; Mavuluri, Jayadev et al. (2018) TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. J Exp Med 215:1023-1034
Sharma, Deepika; Malik, Ankit; Guy, Clifford S et al. (2018) Pyrin Inflammasome Regulates Tight Junction Integrity to Restrict Colitis and Tumorigenesis. Gastroenterology 154:948-964.e8
Malik, Ankit; Kanneganti, Thirumala-Devi (2018) Function and regulation of IL-1? in inflammatory diseases and cancer. Immunol Rev 281:124-137
Place, David E; Kanneganti, Thirumala-Devi (2018) Recent advances in inflammasome biology. Curr Opin Immunol 50:32-38
Zhu, Qifan; Zheng, Min; Balakrishnan, Arjun et al. (2018) Gasdermin D Promotes AIM2 Inflammasome Activation and Is Required for Host Protection against Francisella novicida. J Immunol 201:3662-3668
Kuriakose, Teneema; Kanneganti, Thirumala-Devi (2018) ZBP1: Innate Sensor Regulating Cell Death and Inflammation. Trends Immunol 39:123-134

Showing the most recent 10 out of 39 publications