Cell Discovery (Aug 2023)

The TRIM37 variants in Mulibrey nanism patients paralyze follicular helper T cell differentiation

  • Wangpeng Gu,
  • Jia Zhang,
  • Qing Li,
  • Yaguang Zhang,
  • Xuan Lin,
  • Bingbing Wu,
  • Qi Yin,
  • Jinqiao Sun,
  • Yulan Lu,
  • Xiaoyu Sun,
  • Caiwei Jia,
  • Chuanyin Li,
  • Yu Zhang,
  • Meng Wang,
  • Xidi Yin,
  • Su Wang,
  • Jiefang Xu,
  • Ran Wang,
  • Songling Zhu,
  • Shipeng Cheng,
  • Shuangfeng Chen,
  • Lian Liu,
  • Lin Zhu,
  • Chenghua Yan,
  • Chunyan Yi,
  • Xuezhen Li,
  • Qiaoshi Lian,
  • Guomei Lin,
  • Zhiyang Ling,
  • Liyan Ma,
  • Min Zhou,
  • Kuanlin Xiao,
  • Haiming Wei,
  • Ronggui Hu,
  • Wenhao Zhou,
  • Lilin Ye,
  • Haikun Wang,
  • Jinsong Li,
  • Bing Sun

DOI
https://doi.org/10.1038/s41421-023-00561-z
Journal volume & issue
Vol. 9, no. 1
pp. 1 – 18

Abstract

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Abstract The Mulibrey (Muscle–liver–brain–eye) nanism caused by loss-of-function variants in TRIM37 gene is an autosomal recessive disorder characterized by severe growth failure and constrictive pericarditis. These patients also suffer from severe respiratory infections, co-incident with an increased mortality rate. Here, we revealed that TRIM37 variants were associated with recurrent infection. Trim37 FIN major (a representative variant of Mulibrey nanism patients) and Trim37 knockout mice were susceptible to influenza virus infection. These mice showed defects in follicular helper T (TFH) cell development and antibody production. The effects of Trim37 on TFH cell differentiation relied on its E3 ligase activity catalyzing the K27/29-linked polyubiquitination of Bcl6 and its MATH domain-mediated interactions with Bcl6, thereby protecting Bcl6 from proteasome-mediated degradation. Collectively, these findings highlight the importance of the Trim37-Bcl6 axis in controlling the development of TFH cells and the production of high-affinity antibodies, and further unveil the immunologic mechanism underlying recurrent respiratory infection in Mulibrey nanism.