Potential Roles of Histone Deacetylase 1 and 2 in Regulation of Tubulin Acetylation and Phagocytosis

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Owusu, Christian Adu

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Although histone deacetylases (HDACs) were discovered originally to regulate gene expression through the regulation of the chromatin structure by removal of acetylation of the core histone proteins, a structural component of chromatin, recent studies showed that HDACs also regulate the acetylation of non-histone proteins and play crucial roles in regulating various cellular processes, including gene expression, cellular differentiation, cancer development and immune responses. Recently, we showed that HDAC2 plays a critical role in enhanced inflammatory cytokine IL-1β production macrophages by regulation of NLRP3 inflammasome. In this study, we investigated the involvement of HDAC1 and HDAC2 in macrophage phagocytosis of Mycobacterium tuberculosis, a devastating human intracellular microbial pathogen. Our preliminary data showed that inhibition of HDAC1 and HDAC2 affects phagocytosis by regulation of tubulin acetylation, a process known to be regulated by HDAC6. To understand these unexpected roles of HDAC1 and HDAC2 in regulation of tubulin acetylation, we propose to study the structural basis of chemical inhibitors of HDAC1 and HDAC2 and their potential interaction with HDAC6. In a similar approach, we will also study the potential interaction of the HDAC6 inhibitors with HDAC1 and HDAC2 using molecular docking and other relevant in silico analysis using Texas Supercomputer. The functional significance of the findings from these studies will be confirmed with CRISPR-Cas9 mediated gene editing approach to definitively determine the roles of HDAC1 and HDAC2 in regulation of tubulin acetylation, a critical posttranslational modification of cellular tubulin with significance in cellular functions including phagocytosis. The findings from these studies will help us understand the novel functions of HDACs and guide design novel small molecule-based therapeutics for the better control of tuberculosis infection.


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