K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression

Zhenyue Hao (), Yi Sheng, Gordon S. Duncan, Wanda Y. Li, Carmen Dominguez, Jennifer Sylvester, Yu-Wen Su, Gloria H.Y. Lin, Bryan E. Snow, Dirk Brenner, Annick You-Ten, Jillian Haight, Satoshi Inoue, Andrew Wakeham, Alisha Elford, Sara Hamilton, Yi Liang, Juan C. Zúñiga-Pflücker, Housheng Hansen He, Pamela S. Ohashi and Tak W. Mak ()
Additional contact information
Zhenyue Hao: The Campbell Family Institute for Breast Cancer Research, University Health Network
Yi Sheng: York University
Gordon S. Duncan: The Campbell Family Institute for Breast Cancer Research, University Health Network
Wanda Y. Li: The Campbell Family Institute for Breast Cancer Research, University Health Network
Carmen Dominguez: The Campbell Family Institute for Breast Cancer Research, University Health Network
Jennifer Sylvester: The Campbell Family Institute for Breast Cancer Research, University Health Network
Yu-Wen Su: The Campbell Family Institute for Breast Cancer Research, University Health Network
Gloria H.Y. Lin: The Campbell Family Institute for Breast Cancer Research, University Health Network
Bryan E. Snow: The Campbell Family Institute for Breast Cancer Research, University Health Network
Dirk Brenner: Experimental and Molecular Immunology, Luxembourg Institute of Health
Annick You-Ten: The Campbell Family Institute for Breast Cancer Research, University Health Network
Jillian Haight: The Campbell Family Institute for Breast Cancer Research, University Health Network
Satoshi Inoue: The Campbell Family Institute for Breast Cancer Research, University Health Network
Andrew Wakeham: The Campbell Family Institute for Breast Cancer Research, University Health Network
Alisha Elford: The Campbell Family Institute for Breast Cancer Research, University Health Network
Sara Hamilton: The Campbell Family Institute for Breast Cancer Research, University Health Network
Yi Liang: Princess Margaret Cancer Centre, University Health Network
Juan C. Zúñiga-Pflücker: University of Toronto
Housheng Hansen He: Princess Margaret Cancer Centre, University Health Network
Pamela S. Ohashi: The Campbell Family Institute for Breast Cancer Research, University Health Network
Tak W. Mak: The Campbell Family Institute for Breast Cancer Research, University Health Network

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Here we report that Lys-48-linked ubiquitination of the transcription factor KLF4 mediated by the E3 ligase Mule promotes T-cell entry into S phase. Mule is elevated in T cells upon TCR engagement, and Mule deficiency in T cells blocks proliferation because KLF4 accumulates and drives upregulation of its transcriptional targets E2F2 and the cyclin-dependent kinase inhibitors p21 and p27. T-cell-specific Mule knockout (TMKO) mice develop exacerbated experimental autoimmune encephalomyelitis (EAE), show impaired generation of antigen-specific CD8+ T cells with reduced cytokine production, and fail to clear LCMV infections. Thus, Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo.

Date: 2017
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DOI: 10.1038/ncomms14003

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