HDAC10 negatively regulates NLRP3 inflammasome activation by switching NLRP3 modification from acetylation to ubiquitination

Abstract The NOD-like receptor protein (NLRP)3 inflammasome is the most extensively studied inflammasome actively involved in various inflammatory diseases, however its regulatory mechanism is not fully understood. Histone deacetylase (HDAC)10 is a member of the class II histone deacetylase, while whether it has any regulatory role in inflammasome activation is not known. Here we demonstrated that HDAC10 directly interacted with NLRP3 and induced the deacetylation of NLRP3, which further resulted in the suppression of NLRP3 protein and inhibition of NLRP3 inflammasome activation. Further investigation revealed that deacetylation of NLRP3 by HDAC10 led to the ubiquitination modification and proteasomal degradation of NLRP3, thus decreased the protein level of NLRP3 and further suppressed its activity. In conclusion, this study suggested an acetylation and ubiquitination switch of NLRP3 induced by HDAC10, which revealed a fine-tuned regulation of NLRP3 inflammasome activation. It also provided a potential therapeutic target for NLRP3 inflammasome-associated diseases and facilitated the development of new immunomodulatory therapeutic strategies for NLRP3 inflammasome involved inflammatory diseases.