The proprotein convertase furin regulates the development of thymic epithelial cells to ensure central immune tolerance

• Published in: iScience Vol. 25; no. 10; p. 105233
• Main Authors: Liang, Zhanfeng, Zhang, Zhaoqi, Zhang, Qian, Dong, Xue, Yang, Xiaofeng, Zhang, Jiayu, Lei, Tong, Creemers, John W.M., Zhang, Baojun, Zhao, Yong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 21.10.2022; Elsevier
• Subjects: components of the immune system; immunology; Molecular biology; transcriptomics; transcriptomics; components of the immune system; Molecular biology; immunology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.105233

The generation of mature T cells and establishment of central tolerance is predominantly orchestrated by thymic epithelial cells (TECs). Proprotein convertases are responsible for the proteolysis of proproteins into their mature bioactive counterparts. Here, we found that Furin, a member of the subtilisin/kexin-like PCs family, is highly expressed in TECs compared with other members of this family. TEC-specific deletion of Furin caused severe thymic atrophy and predominantly reduced the number of medullary TECs and thymic tuft cells, and to a less degree, cortical TECs. Furin deletion attenuated the proliferation of TECs, impaired thymopoiesis, and led to autoimmune disorders in mice. Furin promotes the development of TECs via cleavage of proIGF1 receptor and pro-Insulin receptor and the activation of downstream ERK/MAPK and Akt signaling pathways. Thus, this study uncovered the role of furin in TEC development and function and highlighted the importance of post-translational modification of immature proproteins in TEC biology. [Display omitted] •Furin is essential for the development of cTECs, mTECs, and thymic tuft cells•Furin regulates the proliferation of TECs via cleavage of proIGF1R and proIR•Furin expression in TECs is indispensable for multiple stages of thymopoiesis•TEC-expressed Furin is essential for the establishment of central immune tolerance Molecular biology; Immunology; Components of the immune system; Transcriptomics