K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression.
K48-linked KLF4 ubiquitination by E3 ligase Mule controls T-cell proliferation and cell cycle progression.
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DOI：
10.1038/ncomms14003
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发表时间：
2017-01-13
影响因子：
16.6
通讯作者：
Mak TW
中科院分区：
文献类型：
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作者：
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;Zúñiga-Pflücker JC;He HH;Ohashi PS;Mak TW
T细胞增殖受泛素化调控，但其潜在的分子机制仍不清楚。在这里，我们报告说，Lys-48连接泛素化的转录因子KLF 4介导的E3连接酶Mule促进T细胞进入S期。Mule在TCR接合后在T细胞中升高，并且T细胞中的Mule缺陷阻断增殖，因为KLF 4积累并驱动其转录靶点E2 F2和细胞周期蛋白依赖性激酶抑制剂p21和p27的上调。T细胞特异性Mule基因敲除（TMKO）小鼠发生恶化的实验性自身免疫性脑脊髓炎（EAE），显示抗原特异性CD 8 + T细胞的产生受损，细胞因子产生减少，并且不能清除LCMV感染。因此，Mule介导的新型底物KLF 4的泛素化在体内调节T细胞增殖、自身免疫和抗病毒免疫应答。此前已报道E3连接酶Mule通过调节p53遍在蛋白化和降解对B细胞发育和功能至关重要。Hao等人将KLF 4鉴定为Mule的一个新的泛素化靶点，并显示它控制T细胞增殖和自身免疫。
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. The E3 ligase Mule has been previously reported to be essential for B cell development and function by modulating p53 ubiquitination and degradation. Here Hao et al. identify KLF4 as a novel ubiquitination target of Mule and show it controls T cell proliferation and autoimmunity.