DDX3X Cellular Valency Allows Stressed Cells to Make a Live or Die Cell Fate Decision by Regulating Stress Granules and the NLRP3 Inflammasome

Abstract

Abstract Cells of the immune system have to respond to a variety of stressors to help maintain organismal homeostasis. Stress sensing can lead to the assembly of a cytoplasmic membraneless compartment called stress granules (SGs) that helps the cells survive. Cellular stress can also lead to activation of the NLRP3 inflammasome and induction of pyroptosis – a pro-inflammatory programmed cell death. Thus SGs and the NLRP3 inflammasome provide contrasting cell fate choices to a stressed cell – cell survival or pyroptosis. DDX3X is an integral component of SGs [1]. We show that DDX3X promotes the NLRP3 inflammasome activation and ASC speck assembly[2]. Our data suggests that induction of SGs inhibits the NLRP3 inflammasome activation by sequestering the DDX3X molecules. It also suggests that SGs and the NLRP3 inflammasome compete for DDX3X molecules, which makes DDX3X cellular valency critical for this decision making process[3]. Using LPS mediated peritonitis model, we further show that DDX3X promotes and SGs inhibit the NLRP3 inflammasome activation in vivo. Our data points towards a mechanistic paradigm where cells can exploit the cellular valency of biomolecules and a competition between biological processes for common essential factors to make cell fate decisions.