DDX3X Helps Stressed Cells Choose Life or Death

St. Jude Children’s Research Hospital scientists have identified a molecule that plays a pivotal role in determining the fate of cells under stress. The findings were published yesterday in Nature and suggest a possible new approach for the treatment of autoinflammatory and other diseases.

The molecule is DDX3X, an enzyme that, when mutated, is involved in a variety of cancers. DDX3X mutations are also associated with DDX3X syndrome, which is characterized by intellectual disabilities, seizures, autism, poor muscle tone, and slower physical development.

The researchers have now determined that DDX3X also sits at the crossroads between life and death in stressed cells. The molecule helps regulate the innate immune response, which is part of the immune system’s first-responder system. Investigators reported evidence that the availability of DDX3X influences how cells interpret and respond to various stressors with measures meant to ensure cell survival or cell death.

“The findings make DDX3X an attractive target for designing drugs that modify the stress response and restore balance to prevent chronic inflammation and other diseases,” says senior author Thirumala-Devi Kanneganti.

Investigators knew stressed cells needed DDX3X to form membrane-less compartments called stress granules. Stress granules are essential for cell survival. In this study, scientists showed DDX3X was also critical for formation of another membrane-less compartment that led to cell death via a programmed inflammatory cell death pathway.

The researchers have a long-standing interest in the inflammatory cell stress response, particularly regarding a multi-protein complex called the NLRP3 inflammasome, which is activated by infections and other stressors. Activation leads to formation of a membrane-less compartment in cells and secretion of molecules called cytokines that promote inflammation. The process also drives the inflammatory cell death pathway called pyroptosis.

Working first in macrophages and then in mice missing DDX3X gene, researchers reported for the first time that DDX3X interacts with NLRP3 and promotes inflammasome activation. Further research revealed that stress granule formation inhibited the NLRP3 inflammasome by sequestering DDX3X. That limited the molecule’s availability for NLRP3 inflammasome activation and function. Pro-inflammatory cytokine production declined along with cell death via pyroptosis.

“Our model is that formation of stress granules specifically inhibits the availability of DDX3X to activate the NLRP3 inflammasome, inhibiting the pyroptosis cell death pathway,” adds coauthor Kesavardhana Sannula.