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

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

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