Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis

• Published in: Nature communications Vol. 7; no. 1; p. 13353
• Main Authors: Teh, Charis E., Lalaoui, Najoua, Jain, Reema, Policheni, Antonia N., Heinlein, Melanie, Alvarez-Diaz, Silvia, Sheridan, Julie M., Rieser, Eva, Deuser, Stefanie, Darding, Maurice, Koay, Hui-Fern, Hu, Yifang, Kupresanin, Fiona, O’Reilly, Lorraine A., Godfrey, Dale I., Smyth, Gordon K., Bouillet, Philippe, Strasser, Andreas, Walczak, Henning, Silke, John, Gray, Daniel H. D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.11.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/31; 13/95; 38/91; 631/250/1619/554/1898/1271; 631/250/2152/1566/2493; 631/250/516/1909; 64/110; 82/80; 96/34; Animals; Apoptosis; Base Sequence; Cell Differentiation - physiology; Cells; Cells, Cultured; Chemokines; Computational Biology; Cytokines; Dermatitis; Gene Expression Regulation - physiology; Genotype; Homeostasis; Homeostasis - physiology; Humanities and Social Sciences; Lymphocytes; Mice; multidisciplinary; Protein Multimerization; Protein Processing, Post-Translational; RNA - genetics; Science; Science (multidisciplinary); Sequence Analysis, RNA; T-Lymphocytes - classification; T-Lymphocytes - physiology; Thymus Gland - cytology; Tumor necrosis factor-TNF; Ubiquitin - chemistry; Ubiquitin - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination; Australia
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13353

The linear ubiquitin chain assembly complex (LUBAC) is essential for innate immunity in mice and humans, yet its role in adaptive immunity is unclear. Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3 + regulatory T (Treg)-cell development and Treg cell homeostasis. LUBAC activity is not required to prevent TNF-induced apoptosis or necroptosis but is necessary for the transcriptional programme of the penultimate stage of thymocyte differentiation. Treg cell-specific ablation of HOIP causes severe Treg cell deficiency and lethal immune pathology, revealing an ongoing requirement of LUBAC activity for Treg cell homeostasis. These data reveal stage-specific requirements for LUBAC in coordinating the signals required for T-cell differentiation. LUBAC is a ubiquitin ligase complex of HOIL-1, HOIP and SHARPIN important for signal transduction of a range of stimuli. Here the authors define the function of all three LUBAC components in T cell development and homeostasis.