title: Histone deacetylase 6 negatively regulates NLRP3 inflammasome activation.
abstract: Emerging reports demonstrate that deregulated NLRP3 inflammasome activation is implicated in a variety of inflammatory and metabolic disorders, but the molecular mechanism underlying NLRP3 inflammasome regulation remains uncertain. Here, we present evidence that histone deacetylase 6 (HDAC6) inhibits the activation of NLRP3 inflammasome through its direct association with NLRP3. ShRNA-mediated knockdown of HDAC6 in bone marrow-derived macrophages (BMDMs) showed a significant increase in caspase-1 activation and interleukin-1 beta (IL-1β) secretion in response to NLRP3-activating stimulations, but not to absent in melanoma 2 (AIM2)-activating stimulation. In addition, knockdown of HDAC6 in BMDMs enhanced the oligomerization of ASC upon LPS/nigericin stimulation. The augmented NLRP3 inflammasome activation seen in HDAC6-knockdown BMDMs is independent of the deacetylase activity of HDAC6. Instead, HDAC6 directly associates with NLRP3 through its ubiquitin-binding domain. Moreover, PR619 treatment (deubiquitinase inhibitor) resulted in the elevation in the interaction of NLRP3 with HDAC6 and the decrease in NLRP3-dependent caspase-1 activation. Taken together, our results indicate that HDAC6 negatively regulates NLRP3 inflammasome activation through its interaction to ubiquitinated NLRP3.
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Inhwa
authors.initials: I
authors.lastname: Hwang
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Eunju
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
authors.forename: Seon-A
authors.initials: SA
authors.lastname: Jeon
authors.affiliation: Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea. Electronic address: jewookyu@yuhs.ac.
authors.forename: Je-Wook
authors.initials: JW
authors.lastname: Yu
mesh_terms: D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000502:physiology*; D002478:Cells, Cultured; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D058847:Inflammasomes / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014158:Transcription, Genetic; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D025801:Ubiquitin; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Histone deacetylase 6; Inflammasome; NLRP3