A new mechanism of STAT6 acetylation regulating antitumor immune response was found

On September 25, nature communications, an international academic journal, published online the latest research results of "modulation of M2 macrophage polarization by the crosstalk between STAT6 and trim24" by Xiao Yichuan research group of Shanghai Institute of nutrition and health, Chinese Academy of Sciences and Qin Jun research group This study revealed the mechanism of STAT6 acetylation regulating the polarization of macrophage m2 and then affecting the anti-tumor immunity in vivo, and provided a new molecular target for the regulation of anti-tumor immunity Immune cells in tumor microenvironment constitute the immune regulatory system in tumor TAMs (tumor associated macrophases, TAMs) with M2 type characteristics play an important role in inhibiting anti-tumor immunity and promoting tumor progression However, the molecular mechanism of fine regulation of TAMs polarization to M2 is still unclear In this study, it was found that STAT6, the key transcription factor regulating polarization, can undergo CBP mediated k383 site acetylation modification, which can significantly inhibit the transcription activity of STAT6 and the expression of downstream M2 type characteristic genes Subsequently, through the analysis of high-throughput transcriptome sequencing (RNA SEQ) binding protein mass spectrometry, the researchers found that the E3 ubiquitin ligase trim24 of a trim family protein can bind to acetyltransferase CBP, mediate the ubiquitin modification of k63 connection at K119 site of CBP protein, enhance the recruitment of STAT6 by CBP, and promote the acetylation modification of k383 site of STAT6 protein mediated by CBP, thus inhibiting STAT6 Transcription activity and M2 polarization of macrophages Further in vivo studies showed that the deletion of trim24 gene in macrophages inhibited the acetylation modification of STAT6 protein k383 site in TAMs of tumor microenvironment, and further promoted the polarization of TAMs to M2 direction, thus promoting the growth of tumor The researchers also found that TAMs in breast cancer patients' tumor tissues expressed lower trim24 and higher M2 genes than macrophages in normal tissues, and tumor cell conditioned medium could significantly inhibit trim24 expression in human monocytes or macrophages These results suggest that tumor microenvironment may inhibit STAT6 acetylation by inhibiting the expression of trim24 in TAMs, thus further promoting the polarization of TAMs to M2 and maintaining the immunosuppressive microenvironment state in tumors Therefore, targeting STAT6 acetylation or trim24 activity can be used as potential molecular targets for tumor immune intervention Yu Tao, postdoctoral student of Institute of nutrition and health, Gan Shucheng and Zhu Zao, doctoral students, were the co first authors of the paper, and Xiao Yichuan and Qin Jun, researchers, were co correspondents This study was greatly assisted by Mao chaoming, a professor of the Affiliated Hospital of Jiangsu University, Shen kunwei, a professor of Ruijin Hospital, Shanghai Jiaotong University Medical College, etc The research was also supported by the Ministry of science and technology, the National Natural Science Foundation of China and the Chinese Academy of Sciences, as well as the public technology platform and animal platform of the Institute of nutrition and health Recommended conference of editor in chief: 2019 Wuxi International Biomedical forum and the 9th International Conference on cell death & Disease - new drug research and development: http://meeting.bioon.com/bcdd? __token=liaodefeng