Nucleic Acid Sensors and Programmed Cell Death

Nucleic acids derived from microorganisms are powerful triggers for innate immune responses. Proteins called RNA and DNA sensors detect foreign nucleic acids and, in mammalian cells, include RIG-I, cGAS, and AIM2. On binding to nucleic acids, these proteins initiate signaling cascades that activate host defense responses. An important aspect of this defense program is the production of cytokines such as type I interferons and IL-1β. Studies conducted over recent years have revealed that nucleic acid sensors also activate programmed cell death pathways as an innate immune response to infection. Indeed, RNA and DNA sensors induce apoptosis, pyroptosis, and necroptosis. Cell death via these pathways prevents replication of pathogens by eliminating the infected cell and additionally contributes to the release of cytokines and inflammatory mediators. Interestingly, recent evidence suggests that programmed cell death triggered by nucleic acid sensors plays an important role in a number of noninfectious pathologies. In addition to nonself DNA and RNA from microorganisms, nucleic acid sensors also recognize endogenous nucleic acids, for example when cells are damaged by genotoxic agents and in certain autoinflammatory diseases. This review article summarizes current knowledge on the links between nucleic acid sensing and cell death and explores important open questions for future studies in this area.