title: K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression.
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.
authors.affiliation: 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.
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Department of Biology, York University, Toronto, Ontario, Canada M3J 1P3.
authors.forename: Yi
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Duncan
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Wanda Y
authors.initials: WY
authors.lastname: Li
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Carmen
authors.initials: C
authors.lastname: Dominguez
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sylvester
authors.affiliation: 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.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Su
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Gloria H Y
authors.initials: GH
authors.lastname: Lin
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Snow
authors.affiliation: 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.
authors.forename: Dirk
authors.initials: D
authors.lastname: Brenner
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Annick
authors.initials: A
authors.lastname: You-Ten
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Jillian
authors.initials: J
authors.lastname: Haight
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wakeham
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Alisha
authors.initials: A
authors.lastname: Elford
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Sara
authors.initials: S
authors.lastname: Hamilton
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5G 2C1.|Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada M4N 3M5.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Zúñiga-Pflücker
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5G 2C1.
authors.forename: Housheng Hansen
authors.identifier: 0000-0003-2898-3363
authors.initials: HH
authors.lastname: He
authors.affiliation: 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.
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
authors.affiliation: 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.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008216:Lymphocytic Choriomeningitis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D025521:Tumor Suppressor Proteins; C502831:Huwe1 protein, mouse; D044767:Ubiquitin-Protein Ligases