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.
Highlights
T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure
Flow cytometric (FCM) profiling of immunostained thymocytes from T-cell-specific Mule knockout (TMKO) mice showed that the CD4 þ versus CD8 þ populations, as well as the CD25 þ versus CD44 þ subsets among CD4 À CD8 À thymocytes, were comparable to those in Mulefl/fl(y) controls (Fig. 1c, left)
The defective thymic output in TMKO mice may be partially attributed to the lower level of CD44 expression by naive CD4 þ and CD8 þ T cells in these animals
Summary
T-cell proliferation is regulated by ubiquitination but the underlying molecular mechanism remains obscure. Mule-mediated ubiquitination of the novel substrate KLF4 regulates T-cell proliferation, autoimmunity and antiviral immune responses in vivo. (email: Engagement of the T-cell receptors (TCR) of a mature naive T cell triggers signalling leading to activation of kinases and transcription factors[1,2]. Because dysregulation of these pathways impairs homoeostasis and immune responses, and can lead to lymphoma or autoimmunity, they are tightly regulated at multiple levels. To examine Mule’s role in T-cell biology in vivo, we generated T-cell-specific Mule-deficient mice and studied the consequences of Mule inactivation in these mutants and their T cells In vivo, these animals develop severe EAE and show impaired antiviral immune responses. We identify KLF4 as a novel Mule substrate and demonstrate that Mule-mediated regulation of KLF4 controls TCR-mediated T-cell proliferation at the level of cell cycle entry
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