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m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity
Science Advances ( IF 13.6 ) Pub Date : 2021-06-16 , DOI: 10.1126/sciadv.abg0470
Jing Zhou 1, 2, 3 , Xingli Zhang 1, 2 , Jiajia Hu 4 , Rihao Qu 5, 6 , Zhibin Yu 1, 2 , Hao Xu 3 , Huifang Chen 1, 2 , Lichong Yan 3 , Chenbo Ding 1, 2, 3 , Qiang Zou 1 , Youqiong Ye 1 , Zhengting Wang 7 , Richard A Flavell 3, 8 , Hua-Bing Li 1, 2, 3
Affiliation  

N6-methyladenosine (m6A) modification is dynamically regulated by “writer” and “eraser” enzymes. m6A “writers” have been shown to ensure the homeostasis of CD4+ T cells, but the “erasers” functioning in T cells is poorly understood. Here, we reported that m6A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4+ T cells to induce adoptive transfer colitis. In addition, T cell–specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m6A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4+ T cells. These modifications resulted in attenuated CD4+ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m6A eraser in controlling the pathogenicity of CD4+ T cells during autoimmunity.



中文翻译:

m6A 去甲基化酶 ALKBH5 控制 CD4+ T 细胞致病性并促进自身免疫

N 6 -methyladenosine (m 6 A) 修饰由“writer”和“eraser”酶动态调节。m 6已显示“写入器”可确保 CD4 + T 细胞的稳态,但对 T 细胞中的“擦除器”功能知之甚少。在这里,我们报告了 m 6 A 橡皮擦 AlkB 同系物 5 (ALKBH5),但不是 FTO,保持幼稚 CD4 + T 细胞诱导过继性转移性结肠炎的能力。此外,ALKBH5 的 T 细胞特异性消融可以预防实验性自身免疫性脑脊髓炎。在诱导神经炎症期间,ALKBH5 缺乏增加 m 6对干扰素-γ 和 CXC 基序趋化因子配体 2 信使 RNA (mRNA) 进行修饰,从而降低它们在 CD4 + T 细胞中的 mRNA 稳定性和蛋白质表达。这些修改导致减弱的 CD4 + T 细胞反应和减少中性粒细胞向中枢神经系统的募集。我们的研究结果揭示了 ALKBH5 作为 m 6 A 橡皮擦在自身免疫过程中控制 CD4 + T 细胞致病性方面的意想不到的特定作用。

更新日期:2021-06-16
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