HADC5 deacetylates MKL1 to dampen TNF-α induced pro-inflammatory gene transcription in macrophages
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Zilong Li1, Hao Qin1, Jianfei Li1, Liming Yu1, Yuyu Yang1,2 and Yong Xu1
1Key Laboratory of Targeted Intervention of Cardiovascular Disease, Innovative Collaboration Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
2State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
Yuyu Yang, email: email@example.com
Yong Xu, email: firstname.lastname@example.org
Keywords: transcriptional regulation, MKL1, HDAC5, post-translational modification, deacetylation
Received: June 08, 2017 Accepted: September 18, 2017 Published: October 09, 2017
Macrophage-dependent inflammatory response on the one hand functions as a key line of defense in host immunity but on the other hand underlies the pathogenesis of a host of human pathologies when aberrantly activated. Our previous investigations have led to the identification of megakaryocytic leukemia 1 (MKL1) as a key co-factor of NF-κB/p65 participating in TNF-α induced pro-inflammatory transcription in macrophages. How post-translational modifications contribute to the modulation of MKL1 activity remains an underexplored subject matter. Here we report that the lysine deacetylase HDAC5 interacts with and deacetylates MKL1 in cells. TNF-α treatment down-regulates HDAC5 expression and expels HDAC5 from the promoters of pro-inflammatory genes in macrophages. In contrast, over-expression of HDAC5 attenuates TNF-α induced pro-inflammatory transcription. Mechanistically, HDAC5-mediated MKL1 deacetylation disrupts the interaction between MKL1 and p65. In addition, deacetylation of MKL1 by HDAC5 blocks its nuclear translocation in response to TNF-α treatment. In conclusion, our work has identified an important pathway that contributes to the regulation of pro-inflammatory response in macrophages.
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