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Nat Commun. 2017 Jan 13;8:14003. doi: 10.1038/ncomms14003.

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

Author information

1
The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
3
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
4
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.
5
Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3.
6
Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
7
Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, 29, rue Henri Koch, Esch-sur-Alzette L-4354, Luxembourg.
8
Odense Research Center for Anaphylaxis (ORCA), Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense DK-5000 Denmark.
9
Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
10
Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5.

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.

PMID:
28084302
PMCID:
PMC5241832
DOI:
10.1038/ncomms14003
[Indexed for MEDLINE]
Free PMC Article

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