A non-canonical function of Ezh2 preserves immune homeostasis.

Autor:	Vasanthakumar A; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Xu D; Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China.; Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia., Lun AT; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Kueh AJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., van Gisbergen KP; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Iannarella N; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia., Li X; Institute of Ageing Research, Hangzhou Normal University School of Medicine, Hangzhou, China.; Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia., Yu L; Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia., Wang D; Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia., Williams BR; Hudson Institute of Medical Research, Monash University, Clayton, Vic., Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Vic., Australia., Lee SC; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Majewski IJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Godfrey DI; Department of Microbiology and Immunology, The University of Melbourne, Parkville, Vic., Australia.; ARC Centre of Excellence for Advanced Molecular Imaging, The University of Melbourne, Parkville, Vic., Australia., Smyth GK; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Mathematics and Statistics, The University of Melbourne, Parkville, Vic., Australia., Alexander WS; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Herold MJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Kallies A; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Nutt SL; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia nutt@wehi.edu.au rallan@wehi.edu.au.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia., Allan RS; The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia nutt@wehi.edu.au rallan@wehi.edu.au.; Department of Medical Biology, The University of Melbourne, Parkville, Vic., Australia.
Jazyk:	angličtina
Zdroj:	EMBO reports [EMBO Rep] 2017 Apr; Vol. 18 (4), pp. 619-631. Date of Electronic Publication: 2017 Feb 21.
DOI:	10.15252/embr.201643237
Abstrakt:	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. (© 2017 The Authors.)
Databáze:	MEDLINE
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