Immunity https://doi.org/10.1016/j.immuni.2018.08.021 (2018)

Multiple agonists trigger activation of the NLRP3 inflammasome and subsequent caspase-1-dependent maturation and release of the cytokine IL-1β. In Immunity, Guo et al. show that the initiation of cholesterol biosynthesis also activates NLRP3. The transcription factor SREBP2 regulates the expression of genes that encode cholesterol-biosynthetic enzymes; however, membrane-tethered SREBP2 is regulated by SCAP, a proteolytic adaptor that resides in the endoplasmic reticulum. Activation of NLRP3 induces endoplasmic reticulum–to–Golgi translocation of the SREBP2–SCAP complex, which leads to the activation of SREBP2. Reciprocally, depletion of cholesterol, which activates the biosynthetic pathway, also leads to the activation of NLRP3. Notably, NLRP3 requires interaction with SCAP via its NACHT domain to promote translocation of NLRP3 to the Golgi for full activation. Thus, activation of the NLRP3 inflammasome is closely attuned to cellular cholesterol sensing and regulatory feedback pathways through interactions with SCAP.