The NLRC4 inflammasome: The pieces of the puzzle are falling into place

AbstractInflammasomes are intracellular multiprotein platforms for the activation of inflammatory caspases. As components of the innate immune system, they play an important role in the fight against microbes. However, aberrant inflammasome activation has been implicated in auto-inflammatory syndromes. This review focuses on the NLRC4 inflammasome. This is perhaps not the most extensively studied, yet its mechanism of activation is by far the best understood. The NLRC4 inflammasome is activated by several proteins originating from intracellular bacteria, which are first sensed by receptors of the NAIP family. Activated NAIP binds NLRC4, which further recruits dormant NLRC4 molecules in a prion-like oligomerization event. NLRC4 enables a strong amplification of the signal, providing a fast and robust host response. The review also discusses peculiar NLRC4 inflammasome functions in promoting eicosanoid biosynthesis, actin reorganization, and its roles in autoinflammatory syndromes and sterile inflammation. Finally, the first inflammasome-independent engagement of NLRC4 in suppressing melanoma tumor growth is presented. The emerging roles of NLRC4 in various normal and pathological processes demonstrate that there is still plenty to be learned about the NLRC4 mechanism of activation and downstream functions.