School of Mathematics and Statistics - Research Publications

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Author: Godfrey, Dale × End date: 2019 × Start date: 2016 ×

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    A non-canonical function of Ezh2 preserves immune homeostasis
    Vasanthakumar, A ; Xu, D ; Lun, ATL ; Kueh, AJ ; van Gisbergen, KPJM ; Iannarella, N ; Li, X ; Yu, L ; Wang, D ; Williams, BRG ; Lee, SCW ; Majewski, IJ ; Godfrey, DI ; Smyth, GK ; Alexander, WS ; Herold, MJ ; Kallies, A ; Nutt, SL ; Allan, RS (WILEY, 2017-04)
    Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis. T-cell-specific depletion of Ezh2 induces a pronounced expansion of natural killer T (NKT) cells, although Ezh2-deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF, leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2-deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin-independent function of Ezh2 that impacts on the development of the immune system.
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    The linear ubiquitin chain assembly complex: a new function in thymic T cell differentiation and regulatory T cell homeostasis
    Teh, C ; Lalaoui, N ; Jain, R ; Policheni, A ; Heinlein, M ; Alvarez-Diaz, S ; Rieser, E ; Deuser, S ; Koay, H-F ; Hu, Y ; Kupresanin, F ; O'Reilly, L ; Godfrey, D ; Smyth, G ; Bouillet, P ; Strasser, A ; Walczak, H ; Silke, J ; Gray, D (WILEY-BLACKWELL, 2016-08)
    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.