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

Tao Yu, Shucheng Gan, Qingchen Zhu, Dongfang Dai, Ni Li, Hui Wang, Xiaosong Chen, Dan Hou, Yan Wang, Qiang Pan, Jing Xu, Xingli Zhang, Junli Liu, Siyu Pei, Chao Peng, Ping Wu, Simona Romano, Chaoming Mao, Mingzhu Huang, Xiaodong Zhu, Kunwei Shen, Jun Qin () and Yichuan Xiao ()
Additional contact information
Tao Yu: University of Chinese Academy of Sciences
Shucheng Gan: University of Chinese Academy of Sciences
Qingchen Zhu: University of Chinese Academy of Sciences
Dongfang Dai: The Affiliated Hospital of Jiangsu University
Ni Li: University of Chinese Academy of Sciences
Hui Wang: Shanghai Jiaotong University School of Medicine
Xiaosong Chen: Shanghai Jiaotong University School of Medicine
Dan Hou: University of Chinese Academy of Sciences
Yan Wang: University of Chinese Academy of Sciences
Qiang Pan: University of Chinese Academy of Sciences
Jing Xu: University of Chinese Academy of Sciences
Xingli Zhang: University of Chinese Academy of Sciences
Junli Liu: University of Chinese Academy of Sciences
Siyu Pei: University of Chinese Academy of Sciences
Chao Peng: Zhangjiang Lab
Ping Wu: Zhangjiang Lab
Simona Romano: University of Naples, Federico II
Chaoming Mao: The Affiliated Hospital of Jiangsu University
Mingzhu Huang: Fudan University Shanghai Cancer Center
Xiaodong Zhu: Fudan University Shanghai Cancer Center
Kunwei Shen: Shanghai Jiaotong University School of Medicine
Jun Qin: University of Chinese Academy of Sciences
Yichuan Xiao: University of Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-15

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.

Date: 2019
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DOI: 10.1038/s41467-019-12384-2

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