Research Papers:

HADC5 deacetylates MKL1 to dampen TNF-α induced pro-inflammatory gene transcription in macrophages

Zilong Li, Hao Qin, Jianfei Li, Liming Yu, Yuyu Yang _ and Yong Xu

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Oncotarget. 2017; 8:94235-94246. https://doi.org/10.18632/oncotarget.21670

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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

Correspondence to:

Yuyu Yang, email: [email protected]

Yong Xu, email: [email protected]

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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