Abstract
Stat6 is known to drive macrophage M2 polarization. However, how macrophage polarization is fine-tuned by Stat6 is poorly understood. Here, we find that Lys383 of Stat6 is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Mechanistically, Trim24, a CBP-associated E3 ligase, promotes Stat6 acetylation by catalyzing CBP ubiquitination at Lys119 to facilitate the recruitment of CBP to Stat6. Loss of Trim24 inhibits Stat6 acetylation and thus promotes M2 polarization in both mouse and human macrophages, potentially compromising antitumor immune responses. By contrast, Stat6 mediates the suppression of TRIM24 expression in M2 macrophages to contribute to the induction of an immunosuppressive tumor niche. Taken together, our findings establish Stat6 acetylation as an essential negative regulatory mechanism that curtails macrophage M2 polarization.
Highlights
Stat[6] is known to drive macrophage M2 polarization
We identify that Stat[6] is acetylated at Lys[383] by the acetyltransferase CREB-binding protein (CBP) during macrophage M2 polarization
IL-4 stimulation induced the substantial acetylation of lysine residues in Stat[6] in macrophages (Fig. 1a)
Summary
Stat[6] is known to drive macrophage M2 polarization. how macrophage polarization is fine-tuned by Stat[6] is poorly understood. We find that Lys[383] of Stat[6] is acetylated by the acetyltransferase CREB-binding protein (CBP) during macrophage activation to suppress macrophage M2 polarization. Macrophages, a type of functionally diversified immune cell widely spread throughout the whole body of adult mammals, play critical roles in the regulation of homeostasis, inflammation, and antitumor immunity in a tissuespecific and context-dependent manner[1,2,3]. Published studies have suggested that genetic deletion or pharmacological inhibition of Stat[6] dramatically suppresses tumor growth and promotes the antitumor immune responses of macrophages[17,18]. Trim[24] deficiency dramatically suppresses Stat[6] acetylation and promotes M2 polarization and impairs the antitumor immune function of macrophages
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