Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis
Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis
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DOI：
10.1038/s41590-022-01287-y
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发表时间：
2022-08
影响因子：
30.5
通讯作者：
Yuye Yin;Xinyi Yang;Shusheng Wu;Xinyu Ding;Huamin Zhu;Xuehui Long;Yuliang Wang;Sulan Zhai;Yun Chen;N. Che;Jingjing Chen;Xiaoming Wang
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文献类型：
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作者：
Yuye Yin;Xinyi Yang;Shusheng Wu;Xinyu Ding;Huamin Zhu;Xuehui Long;Yuliang Wang;Sulan Zhai;Yun Chen;N. Che;Jingjing Chen;Xiaoming Wang
适当调节B细胞向浆细胞的分化对体液免疫至关重要，同时防止抗体介导的自身免疫；然而，潜在的机制，特别是那些具有病理后果的机制，仍不清楚。在这里，我们发现Jmjd1c （JmjC结构域组蛋白去甲基化酶的一个成员）在B细胞中表达，而在其他免疫细胞中不表达，可以保护小鼠免受类风湿性关节炎（RA）的侵害。在RA患者中，B细胞中JMJD1C表达水平与浆细胞频率和疾病严重程度呈负相关。在机制上，Jmjd1c去甲基化STAT3，而不是组蛋白底物，以抑制浆细胞分化。jmjd1缺失导致STAT3 Lys140高甲基化抑制了与磷酸酶Ptpn6的相互作用，导致STAT3异常持续磷酸化和活性，进而促进浆细胞的产生。缺乏Jmjd1c的生发中心B细胞分化为浆细胞的倾向也显著增加。STAT3 Lys140Arg点突变完全消除了Jmjd1c缺失造成的影响。B细胞中Jmjd1c过表达的小鼠与Jmjd1c缺陷小鼠表现出相反的表型。总的来说，我们的研究揭示了Jmjd1c是浆细胞分化和RA的关键调节因子，也强调了B细胞中STAT3去甲基化修饰的重要性。
Appropriate regulation of B cell differentiation into plasma cells is essential for humoral immunity while preventing antibody-mediated autoimmunity; however, the underlying mechanisms, especially those with pathological consequences, remain unclear. Here, we found that the expression of Jmjd1c, a member of JmjC domain histone demethylase, in B cells but not in other immune cells, protected mice from rheumatoid arthritis (RA). In humans with RA, JMJD1C expression levels in B cells were negatively associated with plasma cell frequency and disease severity. Mechanistically, Jmjd1c demethylated STAT3, rather than histone substrate, to restrain plasma cell differentiation. STAT3 Lys140 hypermethylation caused byJmjd1cdeletion inhibited the interaction with phosphatase Ptpn6 and resulted in abnormally sustained STAT3 phosphorylation and activity, which in turn promoted plasma cell generation. Germinal center B cells devoid of Jmjd1c also acquired strikingly increased propensity to differentiate into plasma cells. STAT3 Lys140Arg point mutation completely abrogated the effect caused by Jmjd1c loss. Mice with Jmjd1c overexpression in B cells exhibited opposite phenotypes to Jmjd1c-deficient mice. Overall, our study revealed Jmjd1c as a critical regulator of plasma cell differentiation and RA and also highlighted the importance of demethylation modification for STAT3 in B cells.