Dissecting the contribution of SREBPs and lipid biosynthesis to inflammasome function

University Of California, San Francisco, San Francisco CA

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Abstract

? DESCRIPTION (provided by applicant): Interleukin-1 family members are key inflammatory cytokines in the innate immune response to infection. While IL-1 is necessary for proper defense against pathogens, the production of this cytokine must be carefully regulated in order to prevent immunopathology. One checkpoint on the release of IL-1 family cytokines is their requirement for post-translational processing by a multi-protein complex known as the inflammasome, which serves as a platform for recruiting and activating the protease caspase-1. Sensing of extracellular bacteria by Toll-like receptors (TLRs) triggers the transcription of il1b mRNA, but IL-1ß is not released until inflammasome sensor proteins recognize bacterial products that have entered the cellular cytosolic compartment. Type I interferons (IFN-I) are known to inhibit inflammasome activity, which partially explains their long-recognized immunosuppressive capacity, although the underlying mechanisms have been unclear. Induction of the enzyme Ch25h, which produces 25-hydroxycholesterol (25-HC) from cholesterol, is a key component of IFN-I- mediated inhibition of inflammasomes. Ch25h is an IFN-I-stimulated gene in macrophages, and deletion of Ch25h results in increased capase-1 activity and release of IL-1ß. 25-HC is a potent suppressor of the Sterol Response Element Binding Protein (SREBP) cholesterol biosynthetic pathway, and Ch25h-deficient macrophages additionally display increased SREBP pathway activity after TLR stimulation. Deletion of SCAP, a protein required for SREBP activation, in macrophages results in decreased inflammasome activity. Based on these data, I aim to characterize how the SREBP pathway positively regulates inflammasomes. Specifically, I propose to determine the necessity and sufficiency of SREBP proteins in augmenting inflammasome function, and to define which step of inflammasome activation they regulate (Aim 1). I also propose to test the hypothesis that SREBPs promote inflammasome function via the production of cholesterol (Aim 2).