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

Zhenyue Hao, Yi Sheng, Gordon S. Duncan, Wanda Y. Li, Carmen Dominguez, Jennifer Sylvester, Yu Wen Su, Gloria H.Y. Lin, Bryan E. Snow, Dirk Brenner, Annick You-Ten, Jillian Haight, Satoshi Inoue, Andrew Wakeham, Alisha Elford, Sara Hamilton, Yi Liang, Juan C. Zúñiga-Pflücker, Housheng Hansen He, Pamela S. OhashiTak W. Mak

Research output: Contribution to journalArticlepeer-review

29 Citations (Scopus)


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.

Original languageEnglish
Article number14003
JournalNature communications
Publication statusPublished - 2017 Jan 13
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy


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