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Bcl10 activates the NF-κB pathway through ubiquitination of NEMO

机译：Bcl10通过NEMO泛素化激活NF-κB途径

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摘要

The NF-κB family of transcription factors is activated in response to many stimuli, including pro-inflammatory cytokines, environmental stresses and, in the case of B and T lymphocytes, by antigenic stimulation. Bcl10 is essential for NF-κB activation by T- and B-cell receptors. T and B lymphocytes from Bcl10-deficient mice fail to activate NF-κB in response to antigen-receptor stimulation and, as a consequence, are unable to proliferate. Bcl10 overexpression is sufficient to activate NF-κB, a process that requires the NF-κB essential modulator NEMO (also known as IKK-γ), which is the regulatory subunit of the IB kinase complex. However, the cellular mechanism by which Bcl10 activates the NF-κB pathway remains unclear. Here we show that Bcl10 targets NEMO for lysine-63-linked ubiquitination. Notably, a mutant form of NEMO that cannot be ubiquiti-nated inhibited Bcl10-induced NF-κB activation. Paracaspase and a ubiquitin-conjugating enzyme (UBC13) were both required for Bcl10-induced NEMO ubiquitination and subsequent NF-κB activation. Furthermore, short interfering RNAs that reduced the expression of paracaspase and UBC13 abrogated the effects of Bcl10. Thus, the adaptor protein Bcl10 promotes activation of NF-κB transcription factors through paracaspase-and UBC13-dependent ubiquitination of NEMO.
机译：转录因子NF-κB家族可响应许多刺激而激活，包括促炎性细胞因子，环境压力，对于B和T淋巴细胞，则通过抗原刺激而被激活。 Bcl10对于T细胞和B细胞受体激活NF-κB至关重要。来自Bcl10缺陷型小鼠的T和B淋巴细胞未能响应抗原受体刺激而激活NF-κB，因此无法增殖。 Bcl10过表达足以激活NF-κB，这一过程需要NF-κB必需调节剂NEMO（也称为IKK-γ），它是IB激酶复合物的调节亚基。但是，Bcl10激活NF-κB途径的细胞机制仍不清楚。在这里，我们显示Bcl10靶向NEMO进行赖氨酸63连接的泛素化。值得注意的是，无法普遍存在的NEMO突变形式抑制了Bcl10诱导的NF-κB活化。 Bcl10诱导的NEMO泛素化和随后的NF-κB激活都需要对半胱天冬酶和泛素结合酶（UBC13）。此外，减少了半胱天冬酶和UBC13表达的短干扰RNA消除了Bcl10的作用。因此，衔接蛋白Bcl10通过半胱天冬酶和依赖UBC13的NEMO泛素化促进NF-κB转录因子的激活。

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