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

  • Experimental and¬†Molecular Immunology
January 13, 2017 By:
  • Hao Z
  • Sheng Y
  • Duncan GS
  • Li WY
  • Dominguez C
  • Sylvester J
  • Su YW
  • Lin GH
  • Snow BE
  • Brenner D
  • You-Ten A
  • Haight J
  • Inoue S
  • Wakeham A
  • Elford A
  • Hamilton S
  • Liang Y
  • Zuniga-Pflucker JC
  • He HH
  • Ohashi PS
  • Mak TW.

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.

2017 Jan. Nat Commun.8:14003.
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