Enzyme-Instructed Intracellular Peptide Assemblies

Throughout the biological world, a 30 A hydrophobic film typically delimits the environments that serve as the margin between life and death for individual cells. Biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functionalities of their individual membranes?

The NLRP3 inflammasome is a multimeric protein complex that initiates an inflammatory form of cell death and triggers the release of proinflammatory cytokines IL-1β and IL-18. The NLRP3 inflammasome has been implicated in a wide range of diseases, including Alzheimer’s disease, Prion diseases, type 2 diabetes, and some infectious diseases. It has been found that a variety of stimuli including danger-associated molecular patterns (DAMPs, such as silica and uric acid crystals) and pathogen-associated molecular patterns (PAMPs) can activate NLRP3 inflammasome, but the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Understanding the mechanisms of NLRP3 activation will enable the development of its specific inhibitors to treat NLRP3-related diseases. In this review, we summarize current understanding of the regulatory mechanisms of NLRP3 inflammasome activation as well as inhibitors that specifically and directly target NLRP3.

The binding of DNA to cyclic GMP-AMP synthase (cGAS) leads to the production of the secondary messenger cyclic GMP-AMP (cGAMP), which activates innate immune responses. Here, we show that DNA binding to cGAS robustly induced the formation of liquid-like droplets in which cGAS was activated. The disordered and positively charged cGAS N-terminus enhanced cGAS–DNA phase separation by increasing the valencies of DNA binding. Long DNA was more efficient in promoting cGAS liquid phase separation and cGAS enzyme activity than short DNA. Moreover, free zinc ion enhanced cGAS enzyme activity both in vitro and in cells by promoting cGAS–DNA phase separation. These results demonstrated that the DNA-induced phase transition of cGAS promotes cGAMP production and innate immune signaling.