CAS Key Laboratory of Tissue Microenvironment and Tumor, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China.
Institute of Oncology and Department of Nuclear Medicine, The Affiliated Hospital of Jiangsu University, 438 Jiefang Road, Zhenjiang, 212001, China.
Nat Commun. 2019 Sep 25;10(1):4353. doi: 10.1038/s41467-019-12384-2.
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.
Stat6 已知可驱动巨噬细胞 M2 极化。然而，Stat6 如何精细调控巨噬细胞极化尚不清楚。在这里，我们发现 Stat6 的赖氨酸 383 在巨噬细胞激活过程中被乙酰转移酶 CREB 结合蛋白（CBP）乙酰化，以抑制巨噬细胞 M2 极化。在机制上，Trim24，一种与 CBP 相关的 E3 连接酶，通过催化 CBP 在赖氨酸 119 上的泛素化来促进 Stat6 的乙酰化，从而促进 CBP 招募到 Stat6。Trim24 的缺失抑制了 Stat6 的乙酰化，从而促进了小鼠和人类巨噬细胞中的 M2 极化，可能会损害抗肿瘤免疫反应。相比之下，Stat6 介导了对 M2 巨噬细胞中 TRIM24 表达的抑制，有助于诱导免疫抑制性肿瘤微环境。总之，我们的研究结果确立了 Stat6 乙酰化为抑制巨噬细胞 M2 极化的必要负调控机制。
