2. Academic Validation
  3. Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis

Jmjd1c demethylates STAT3 to restrain plasma cell differentiation and rheumatoid arthritis

  • Nat Immunol. 2022 Sep;23(9):1342-1354. doi: 10.1038/s41590-022-01287-y.
Yuye Yin  # 1,  Xinyi Yang  # 1,  Shusheng Wu  # 1,  Xinyu Ding 1,  Huamin Zhu 1,  Xuehui Long 1,  Yuliang Wang 1,  Sulan Zhai 1,  Yun Chen 1,  Nan Che 2,  Jingjing Chen 3,  Xiaoming Wang 4
Affiliations

Affiliations

  • 1 Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, NHC Key Laboratory of Antibody Technique, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China.
  • 2 Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. nche3850@126.com.
  • 3 Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, NHC Key Laboratory of Antibody Technique, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China. chenjingjing@njmu.edu.cn.
  • 4 Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases, NHC Key Laboratory of Antibody Technique, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Personalized Cancer Medicine, Nanjing Medical University, Nanjing, China. xmwang@njmu.edu.cn.
  • # Contributed equally.
PMID: 35995859 DOI: 10.1038/s41590-022-01287-y
Abstract

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 by Jmjd1c deletion 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.

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