[en] 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Hao, Zhenyue; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1 ; The Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, and Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, Ontario, Canada M5S3E1
Sheng, Yi; Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3
Duncan, Gordon S; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Li, Wanda Y; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Dominguez, Carmen; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Sylvester, Jennifer; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Su, Yu-Wen; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
Lin, Gloria H Y; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Snow, Bryan E; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, 29, rue Henri Koch, Esch-sur-Alzette L-4354, Luxembourg ; Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense DK-5000 Denmark
You-Ten, Annick; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Haight, Jillian; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Inoue, Satoshi; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Wakeham, Andrew; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Elford, Alisha; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Hamilton, Sara; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9
Liang, Yi; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9
Zúñiga-Pflücker, Juan C; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1 ; Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5
He, Housheng Hansen ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1
Ohashi, Pamela S; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1 ; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1
Mak, Tak W; The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 ; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1 ; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1
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