Nemo-like Kinase Drives Foxp3 Stability and Is Critical for Maintenance of Immune Tolerance by Regulatory T Cells
Year: 2019
Type: article
Abstract: The Foxp3 transcription factor is a crucial determinant of both regulatory T (T REG ) cell development and their functional maintenance. Appropriate modulation of tolerogenic immune responses therefore requires the tight regulation of Foxp3 transcriptional output, and this involves both transcriptional and post-translational regulation. Here, we show that during T cell activation, phosphorylation of Foxp3 in T REG cells can be regulated by a TGF-β activated kinase 1 (TAK1)-Nemo-like kinase (NLK) signaling pathway. NLK interacts and phosphorylates Foxp3 in T REG cells, resulting in the stabilization of protein levels by preventing association with the STUB1 E3-ubiquitin protein ligase. Conditional T REG cell NLK-knockout (NLK ΔTREG ) results in decreased T REG cell-mediated immunosuppression in vivo , and NLK-deficient T REG cell animals develop more severe experimental autoimmune encephalomyelitis. Our data suggest a molecular mechanism, in which stimulation of TCR-mediated signaling can induce a TAK1-NLK pathway to sustain Foxp3 transcriptional activity through the stabilization of protein levels, thereby maintaining T REG cell suppressive function.
Source: Cell Reports
Authors: Veerle Fleskens, Carlos M. Minutti, Xingmei Wu, Ping Wei, Cornelieke E.G.M. Pals, James McCrae, Saskia Hemmers, Vincent Groenewold, Harm-Jan Vos, Alexander Rudensky, Fan Pan, Huabin Li, Dietmar M. Zaiss, Paul J. Coffer
Institutions: Utrecht University, University Medical Center Utrecht, University of Edinburgh, Shanghai Medical College of Fudan University, Fudan University, Eye & ENT Hospital of Fudan University, Children's Hospital of Chongqing Medical University, Memorial Sloan Kettering Cancer Center, Howard Hughes Medical Institute, Johns Hopkins University, Johns Hopkins Medicine, Sidney Kimmel Comprehensive Cancer Center
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,680
Funders: U.S. Department of Defense, Howard Hughes Medical Institute, Melanoma Research Alliance, Shanghai Association for Science and Technology, European Commission, National Natural Science Foundation of China, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Science and Technology Commission of Shanghai Municipality, ReumaNederland, Dutch Arthritis Association, National Institutes of Health, Medical Research Council, European Research Council, National Cancer Institute, National Institute of Allergy and Infectious Diseases
Awards: G1600759607, The Role of EOS in Regulatory T-cell Biology., Use of EGF-R antagonists for the treatment of infections and tumour growth, G5644443445, Metabolic regulation of T cell fate and tumor immunity, Epidermal growth factor receptor antagonists: Effect on regulatory T cells, and use as an adjuvant treatment for infectious disease, G8279586403, E3 ligase mediated control of Foxp3 expression and immune suppression-mechanisms and potential as immunotherapeutic target, G8812218988, Use of EGF-R antagonists for the treatment of chronic infections and tumor growth, Cancer Center Support Grant
OpenAlex ID: W2924837719