Targeting HDAC6-Mediated Deacetylation of STAT4 Is Critical for T helper Type 1 Cell Differentiation and Capability

We report that inhibition and knockout of HDAC6 enhanced Th1 cell differentiation, and decreased Listeria monocytogenes infection in mice. Mechanistically, HDAC6 directly deacetylated CBP-catalyzed acetylation on STAT4 lysine 667 via its enzymatic activity, which is required for IL-12-induced phosphorylation on STAT4. Stat4K667R mutant mice lost the ability to normally differentiate Th1 cell and developed sever L. monocytogenes infection. Our study identifies the STAT4 acetylation on K667 modified dynamically by CBP and HDAC6, as an essential signaling event for Th1 cell differentiation and defense of intracellular pathogen infections, highlighting the therapeutic potential of HDAC6 inhibition for controlling intracellular pathogen infections. Overall design: mRNA profiles in CD4+ Th0 and Th1 cells of wild type (WT), Stat4-/- and Stat4-K667R mice were generated by deep sequencing, in triplicate, using Illumina HiSeq2500.