Discover the molecule that helps stressed cells choose between life and death

Scientists at the St. Jude Children's Research Hospital have identified a molecule that plays a crucial role in determining the fate of cells under stress, much like a Roman emperor deciding the fate of gladiators in the Coliseum . The results appear today in the newspaper Nature and suggest a possible new approach for the treatment of auto-inflammatory and other diseases.

The molecule is DDX3X, an enzyme that, when mutated, is implicated in a variety of cancers, such as breast, lung and brain cancers, including medulloblastoma, the most common pediatric brain malignancy. . DDX3X mutations are also associated with DDX3X syndrome, characterized by intellectual disabilities, seizures, autism, weak muscle tone, and slower physical development.

The researchers determined that DDX3X is also at a 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 have reported evidence that the availability of DDX3X influences how cells interpret and respond to various stressors through measures to ensure cell survival or death.

"The results make DDX3X an attractive target for the design of drugs that alter the stress response and restore balance to prevent chronic inflammation and other diseases," said the reporter. Corresponding author Thirumala-Devi Kanneganti, Ph.D., member of the St. Jude Department of Immunology. The cor-matching author is Richard Gilbertson, M.D., Ph.D., formerly of St. Jude and today Cancer Research UK Cambridge Institute.

Stress response

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

"The findings represent a major advance in understanding innate immunity and cellular stress response, demonstrating that the DDX3X-mediated interaction between two membrane-free compartments allows for different cell fates," he said. Kanneganti.

Inflammation

Kanneganti's laboratory has long been interested in the response to inflammatory cell stress, particularly to a protein complex called the NLRP3 inflammasome.

Infections and other stressors activate NLRP3. The activation leads to the formation of a compartment without membrane in the cells and the secretion of molecules called cytokines that promote inflammation. The process also drives the pathway of inflammatory cell death called pyroptosis. The overactivation of the NLRP3 inflammasome gives rise to cancers and auto-inflammatory diseases such as atherosclerosis and type 2 diabetes.

Since the cells also react to stress by forming stress granules, Kanneganti and his colleagues were curious to establish a possible link between the activation of the inflammasome and the assembly of stress granules.

The search led to DDX3X.

The proof

Working first in white blood cells called macrophages in the laboratory, and then in mice with myeloid cells devoid of the Ddx3x gene, the researchers reported for the first time that DDX3X was interacting with NLRP3 and promoting the activation of the gene. # 39; inflammasome.

Subsequent research revealed that the formation of stress granules inhibited the NLRP3 inflammasome by sequestering DDX3X. This limited the availability of the molecule for the activation and function of the NLRP3 inflammasome. Proinflammatory cytokine production decreased in parallel with cell death by pyroptosis.

"The results suggest that the competition for DDX3X between stress granulation formation and the activation of NLRP3's inflammmasome allows macrophages to interpret stress signals and choose their fate," he said. said Parimal Samir, Ph.D., of St. Jude.

Kesavardhana Sannula, Ph.D., from St. Jude: "Our model is that stress granule formation specifically inhibits the availability of DDX3X to activate the NLRP3 inflammasome, thus inhibiting the pathway of cell death by pyroptosis. "