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

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

doi:10.18632/oncotarget.21670

Abstract

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.

Highlights

A key difference between prokaryotes and eukaryotes is the presence of a mature and full-fledged post-translational modification (PTM) machinery in the latter organisms [1]
Cao et al have previously reported that Myocardin, a transcriptional modulator closely related to megakaryocytic leukemia 1 (MKL1), is deacetylated by histone deacetylase 5 (HDAC5) in smooth muscle cells [21]
How HDAC5 contributes to pathophysiological processes following embryogenesis remains incompletely understood because most studies so far have focused on the regulatory role HDAC5 plays in cardiac hypertrophy by acting as a www.impactjournals.com/oncotarget co-repressor for MEF2 [25]

Summary

Introduction

A key difference between prokaryotes and eukaryotes is the presence of a mature and full-fledged post-translational modification (PTM) machinery in the latter organisms [1]. Modulation of TF activity via PTM represents a paradigm in transcriptional regulation. Acetylation, for instance, can be catalyzed by lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) [4]. Both the p50 subunit and the p65 subunit of NF-κB can be acetylated the responsible KATs appear to be different depending on the context [5, 6]. Several different KDACs including SIRT1 [7], SIRT2 [8], HDAC1 [9], and HDAC6 [10] are known to possess deacetylase activities towards NF-κB

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Conclusion