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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

28 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 - 13 Jan 2017


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