Promyelocytic Leukemia Protein Interacts with the Apoptosis-associated Speck-like Protein to Limit Inflammasome Activation

The apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) is an essential component of several inflammasomes, multiprotein complexes that regulate caspase-1 activation and inflammation. We report here an interaction between promyelocytic leukemia protein (PML) and ASC. We observed enhanced formation of ASC dimers in PML-deficient macrophages. These macrophages also display enhanced levels of ASC in the cytosol. Furthermore, IL-1β production was markedly enhanced in these macrophages in response to both NLRP3 and AIM2 inflammasome activation and following bone marrow-derived macrophage infection with herpes simplex virus-1 (HSV-1) and Salmonella typhimurium. Collectively, our data indicate that PML limits ASC function, retaining ASC in the nucleus. Background: ASC is the common adaptor of caspase-1 activation in several inflammasomes. Results: A novel interaction between PML and ASC is identified. PML-deficient macrophages display enhanced levels of IL-1β secretion and higher levels of ASC in the cytosol. Conclusion: PML retains ASC in the nucleus limiting inflammasome activation. Significance: Understanding the regulation of inflammasome components will aid in the development of therapeutics to alleviate IL-1β-mediated diseases.