Zinc homeostasis regulates caspase activity and inflammasome activation
Xiao Gong, W. Gu, Shuo Fu, Gonglu Zou, Zhengfan Jiang
Abstract
Inflammasome activation drives pyroptotic cell death and the release of inflammatory cytokines, and many diseases involve its overactivation. Zinc is essential for all organisms as a trace element, but its functions in innate immunity remain undefined. Here, we reported that Zn2+ inhibits caspase-1 to hinder inflammasome activation. We first identified the zinc exporter solute carrier family 30 member 1 (SLC30A1) as an inflammasome regulator, using a genome-wide CRISPR-Cas9-mediated screen. SLC30A1 deficiency suppressed multiple inflammasomes by increasing intracellular levels of Zn2+, which bound and inhibited caspase-1 at its active site residues H237, C244 and C285. Mutation of these residues almost completely blocked zinc binding. Similarly, Zn2+ also inhibited caspase-4/5/11-mediated noncanonical inflammasome activation. Importantly, zinc supplementation significantly relieved cecal ligation and puncture (CLP)-induced sepsis, Imiquimod (IMQ)-induced psoriasis and Alzheimer's disease. Thus, zinc might be used to treat inflammasome-related diseases as a broad-spectrum inflammasome inhibitor.