St. Jude Children's Research Hospital researchers have identified a molecule that plays an important role in determining the fate of cells under stress, much like a Roman emperor who determines the fate of gladiators in the coliseum. The results are presented today in the journal Nature and suggest a possible new method for the treatment of autoinflammatory and other diseases.
The molecule is DDX3X, an enzyme that, when mutated, is involved in various cancers, such as breast, lung and brain, including medulloblastoma, the most common malignant pediatric brain tumor. DDX3X mutations are also associated with DDX3X syndrome, which is characterized by intellectual disabilities, seizures, autism, poor muscle tone and slower physical development.
Researchers have determined that DDX3X also sits at the intersection of life and death in stressed cells. The molecule helps regulate the innate immune response, which is part of the immune system's first response system. Investigators reported evidence that the availability of DDX3X affects how cells interpret and respond to various stressors with measures designed to ensure cell survival or cell death.
"The results make DDX3X an attractive target for designing drugs that modify the stress response and restore balance to prevent chronic inflammation and other diseases," said corresponding author Thirumala-Devi Kanneganti, Ph.D., a member of St. Jude Department of Immunology. The co-author is Richard Gilbertson, MD, Ph.D., formerly of St. Jude and now of Cancer Research UK Cambridge Institute.
Investigators knew that stressed cells needed DDX3X to form membrane-free compartments called stress granules. Stress granules are important for cell survival. In this study, researchers showed that DDX3X was also critical for the formation of another membrane-free compartment that led to cell death via a programmed inflammatory cell death pathway.
"The results represent a major advance in understanding innate immunity and cell voltage responses, showing that DDX3X-mediated interaction between two membrane-free compartments enables different cell formats," Kanneganti said.
Kanneganti's laboratory has a longstanding research interest in the inflammatory cell stress response, especially a multi-protein complex called the NLRP3 inflammasome.
Infections and other stressors activate NLRP3. Activation leads to the formation of a membrane-free compartment in cells and secretion of molecules called cytokines that promote inflammation. The process also drives the inflammatory cell death pathway called pyroptosis. Overactivation of the NLRP3 inflammasome causes cancer and autoinflammatory diseases such as atherosclerosis and type 2 diabetes.
Since cells also respond to stress with the formation of stress granules, Kanneganti and her colleagues were curious about a possible link between inflammasome activation and stress granules.
The search led to DDX3X.
First works in white blood cells called macrophages in the laboratory and then in mice with myeloid cells lacking the Ddx3x gene, researchers first reported that DDX3X interacts with NLRP3 and promotes inflammation activation.
Further research showed that formation of stress granules inhibited the NLRP3 inflammasome by sequestration of DDX3X. The limited molecule's availability for NLRP3 inflammasome activation and function. Pro-inflammatory cytokine production decreased along with cell death via pyroptosis.
"The results suggest that competition for DDX3X between stress granule formation and NLRP3 inflammasome activation allows macrophages to interpret stress signals and select their fate," says Parimal Samir, Ph. D., from St. Jude.
Added to Kesavardhana Sannula, Ph.D., St. St. Judas: "Our model is that the formation of stress granules specifically inhibits the availability of DDX3X to activate the NLRP3 inflammasome, inhibiting the pyroptosis cell death pathway."
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Parimal Samir et al, DDX3X acts as a live-or-die checkpoint in stressed cells by regulating the NLRP3 inflammasome, Nature (201
Meet the molecule that helps stressed cells decide between life and death (2019, September 11)
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