RNF213 promotes Treg cell differentiation by facilitating K63-linked ubiquitination and nuclear translocation of FOXO1

• Published in: Nature communications Vol. 15; no. 1; pp. 5961 - 13
• Main Authors: Yang, Xiaofan, Zhu, Xiaotong, Sheng, Junli, Fu, Yuling, Nie, Dingnai, You, Xiaolong, Chen, Yitian, Yang, Xiaodan, Ling, Qiao, Zhang, Huili, Li, Xiaomin, Hu, Shengfeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 13/95; 14; 38; 38/77; 42; 45; 631/250/127/1212; 631/250/1619/554/1898/1271; 631/337/572; 631/45/612/1254; 64/60; 82/80; Active Transport, Cell Nucleus; Animals; Autoimmune diseases; CD4 antigen; Cell Differentiation; Cell Nucleus - metabolism; Differentiation (biology); Encephalomyelitis, Autoimmune, Experimental - genetics; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Female; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Forkhead protein; FOXO1 protein; HEK293 Cells; Helper cells; Humanities and Social Sciences; Humans; Immune response; Immune system; Interferon-beta - metabolism; Lymphocytes; Lymphocytes T; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Multiple sclerosis; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Multiple Sclerosis - pathology; Nuclear transport; Protein transport; Proteins; RING finger proteins; Science; Science (multidisciplinary); T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Therapeutic targets; Translocation; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; β-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50392-z

Autoreactive CD4 + T helper cells are critical players that orchestrate the immune response both in multiple sclerosis (MS) and in other neuroinflammatory autoimmune diseases. Ubiquitination is a posttranslational protein modification involved in regulating a variety of cellular processes, including CD4 + T cell differentiation and function. However, only a limited number of E3 ubiquitin ligases have been characterized in terms of their biological functions, particularly in CD4 + T cell differentiation and function. In this study, we found that the RING finger protein 213 (RNF213) specifically promoted regulatory T (Treg) cell differentiation in CD4 + T cells and attenuated autoimmune disease development in an FOXO1-dependent manner. Mechanistically, RNF213 interacts with Forkhead Box Protein O1 (FOXO1) and promotes nuclear translocation of FOXO1 by K63-linked ubiquitination. Notably, RNF213 expression in CD4 + T cells was induced by IFN-β and exerts a crucial role in the therapeutic efficacy of IFN-β for MS. Together, our study findings collectively emphasize the pivotal role of RNF213 in modulating adaptive immune responses. RNF213 holds potential as a promising therapeutic target for addressing disorders associated with Treg cells. Multiple sclerosis and some other neuroinflammatory diseases are associated with aberrant CD4 + T cell differentiation and regulatory T cell function. Here authors show that the E3 ubiquitin ligase RNF213 is central to both physiological and pathologic CD4 + T cell differentiation, and finetunes IFN-β responses in multiple sclerosis.