DDX3X Sits at the Crossroads of Liquid-Liquid and Prionoid Phase Transitions Arbitrating Life and Death Cell Fate Decisions in Stressed Cells

Abstract

The crosstalk between cellular stress responses and innate immune signaling pathways remains poorly understood. Cells can respond to stressors by assembling stress granules that store 40S ribosomes, translation initiation factors, and mRNAs, and allow the cell to survive. Some stressors can activate the NLRP3 inflammasome, which leads to pyroptotic cell death. Stress granules and the NLRP3 inflammasome provide distinct cell fate choices to the cell. These complexes also involve distinct types of phase transitions-liquid-liquid phase separation for stress granules and prionoid phase transition for the NLRP3 inflammasome. We recently reported that DDX3X modulates this crosstalk by acting as a common essential factor for NLRP3 inflammasome activation and stress granule assembly. Here, we discuss the role of DDX3X in modulating the liquid-liquid phase separation and prionoid phase transition required for making cell fate decisions under stress conditions.

Keywords: DDX3X; NLRP3; PANoptosis; cell fate decisions; inflammasome; stress granules.

FIG. 1.

Subcellular localization of DDX3X allows the cell to make life and death decisions. (A) DDX3X localization in stress granules promotes stress granule assembly and cell survival. (B) DDX3X association with the NLRP3 inflammasome promotes a type of proinflammatory programmed cell death called pyroptosis.