Thymocyte-specific truncation of the deubiquitinating domain of CYLD impairs positive selection in a NF-kappaB essential modulator-dependent manner

The Journal of Immunology : Official Journal of the American Association of Immunologists
Ageliki TsagaratouGeorge Mosialos

Abstract

The cylindromatosis tumor suppressor gene (Cyld) encodes a deubiquitinating enzyme (CYLD) with immunoregulatory function. In this study, we evaluated the role of Cyld in T cell ontogeny by generating a mouse (Cyld(Delta9)) with a thymocyte-restricted Cyld mutation that causes a C-terminal truncation of the protein and reciprocates catalytically inactive human mutations. Mutant mice had dramatically reduced single positive thymocytes and a substantial loss of peripheral T cells. The analyses of polyclonal and TCR-restricted thymocyte populations possessing the mutation revealed a significant block in positive selection and an increased occurrence of apoptosis at the double-positive stage. Interestingly, in the context of MHC class I and II restricted TCR transgenes, lack of functional CYLD caused massive deletion of thymocytes that would have been positively selected, which is consistent with an impairment of positive selection. Biochemical analysis revealed that Cyld(Delta9) thymocytes exhibit abnormally elevated basal activity of NF-kappaB and JNK. Most importantly, inactivation of NF-kappaB essential modulator fully restored the NF-kappaB activity of Cyld(Delta9) thymocytes to physiologic levels and rescued their developmenta...Continue Reading

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Citations

Dec 2, 2010·Cell Research·Edward W Harhaj, Vishva M Dixit
Mar 7, 2012·Microbiology and Molecular Biology Reviews : MMBR·Jonathan Maelfait, Rudi Beyaert
Mar 26, 2016·Cell Research·Hongbo Hu, Shao-Cong Sun
May 20, 2017·Critical Reviews in Biochemistry and Molecular Biology·Petra EbnerFumiyo Ikeda
Jul 29, 2018·Frontiers of Medicine·Xiao-Dong Yang, Shao-Cong Sun
Mar 23, 2012·Immunological Reviews·Edward W Harhaj, Vishva M Dixit
Jul 6, 2011·European Journal of Immunology·Ageliki TsagaratouGeorge Mosialos
Sep 5, 2020·International Journal of Molecular Sciences·Gizem CelebiOzlem Kutlu
Aug 28, 2020·Frontiers in Oncology·Xing HuangXueli Bai

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