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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amino Acid Motifs
-
Animals
-
Cell Proliferation*
-
Female
-
Humans
-
Kruppel-Like Factor 4
-
Kruppel-Like Transcription Factors / chemistry*
-
Kruppel-Like Transcription Factors / genetics
-
Kruppel-Like Transcription Factors / immunology
-
Kruppel-Like Transcription Factors / metabolism*
-
Lymphocytic Choriomeningitis / genetics
-
Lymphocytic Choriomeningitis / immunology
-
Lymphocytic Choriomeningitis / physiopathology
-
Lymphocytic Choriomeningitis / virology
-
Lymphocytic choriomeningitis virus / physiology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
T-Lymphocytes / cytology*
-
T-Lymphocytes / enzymology*
-
T-Lymphocytes / immunology
-
T-Lymphocytes / metabolism
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism*
-
Ubiquitin-Protein Ligases / genetics
-
Ubiquitin-Protein Ligases / metabolism*
-
Ubiquitination
Substances
-
KLF4 protein, human
-
Klf4 protein, mouse
-
Kruppel-Like Factor 4
-
Kruppel-Like Transcription Factors
-
Tumor Suppressor Proteins
-
Huwe1 protein, mouse
-
Ubiquitin-Protein Ligases