Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24

Author:

Yu TaoORCID,Gan Shucheng,Zhu Qingchen,Dai Dongfang,Li Ni,Wang Hui,Chen Xiaosong,Hou Dan,Wang Yan,Pan Qiang,Xu Jing,Zhang Xingli,Liu Junli,Pei Siyu,Peng ChaoORCID,Wu Ping,Romano SimonaORCID,Mao Chaoming,Huang Mingzhu,Zhu Xiaodong,Shen Kunwei,Qin JunORCID,Xiao YichuanORCID

Abstract

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.

Funder

National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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