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Molecular and biological studies of a novel regulatory component of the IkappaB kinase complex essential for the NF-kappaB signaling pathway.

机译：对NF-κB信号传导通路必不可少的IkappaB激酶复合物的新型调节成分的分子和生物学研究。

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摘要

The family of NF-κB transcription factors play a central role in innate and adaptive immunity, apoptosis, development and cancer. The mechanism necessary to trigger NF-κB activation in response to a plethora of external signals involves phosphorylation, ubiquitination and degradation of the IκB proteins. Previously, purification of cytokine responsive IkappaB kinase (IKK) activity revealed a high molecular weight multi-protein complex responsible for phosphorylation of the IκB proteins. This complex was predicted to contain several subunits, including two catalytic kinases, IKK1/α (IKK1) and IKK2/β (IKK2) and an essential regulatory subunit, NEMO/IKKγ/IKKAP1 (NEMO). Here, we describe the characterization of a novel regulatory subunit, ELKS, that was co-purified during purification of the IKK complex. Co-immunoprecipitation studies confirm that ELKS is a core component of the high molecular weight IKK signalsome that associates directly with IKK1 and IKK2, but not with NEMO. Utilizing RNA interference (RNAi) to silence ELKS gene expression, we demonstrate that IKK activation is severely impaired in the absence of ELKS leading to a subsequent loss of NF-κB regulated gene expression in response to cytokines, and the inability to protect from programmed cell death. This demonstrates that ELKS is an indispensable component of the IKK complex playing a vital role in NF-κB activation.; We describe a role for ELKS in facilitating the recruitment of IκBα to the IKK complex. An amino-terminal deletion mutant of ELKS can elicit IKK and NF-κB activation in the absence of cytokine induction, advancing insight into IKK activation mechanisms. The regulatory subunits, NEMO and ELKS, are non-redundant essential components for IKK and NF-κB activation. The IKK complex was also found to be associated with the trafficking protein Rab6 through a common association with ELKS.; Finally, a novel member of the ELKS protein family (human) is described here, ELKS2. ELKS2 is strikingly similar to ELKS in its sequence (72% amino acid identity), IKK activating potential and interacting proteins. ELKS2 can influence expression of specific NF-κB target genes, TNFα. The striking difference between the two proteins is their tissue distribution. Future studies into this gene family will give valuable insight into the regulation of IKK and NF-κB transcription in diverse tissues.
机译：NF-κB转录因子家族在先天和适应性免疫，细胞凋亡，发育和癌症中起着核心作用。响应大量外部信号而触发NF-κB激活的必要机制涉及IκB蛋白的磷酸化，泛素化和降解。以前，细胞因子应答性IkappaB激酶（IKK）活性的纯化显示了负责IκB蛋白磷酸化的高分子量多蛋白复合物。预测该复合物包含几个亚基，包括两个催化激酶IKK1 /α（IKK1）和IKK2 /β（IKK2）和一个必需的调节亚基NEMO /IKKγ/ IKKAP1（NEMO）。在这里，我们描述了IKK复合物纯化过程中被共同纯化的新型调节亚基ELKS的表征。免疫共沉淀研究证实，ELKS是高分子量IKK信号体的核心成分，它直接与IKK1和IKK2相关，而与NEMO不相关。利用RNA干扰（RNAi）沉默ELKS基因表达，我们证明了在没有ELKS的情况下IKK激活受到严重损害，从而导致随后因细胞因子而丧失了NF-κB调控基因表达，并且无法从程序化细胞中保护死亡。这表明ELKS是IKK复合物必不可少的组成部分，在NF-κB激活中起着至关重要的作用。我们描述了ELKS在促进IκBα向IKK复合物募集中的作用。在没有细胞因子诱导的情况下，ELKS的氨基末端缺失突变体可以引起IKK和NF-κB激活，从而进一步了解IKK激活机制。调节亚基NEMO和ELKS是IKK和NF-κB激活的非冗余必需成分。还发现IKK复合物通过与ELKS的共同缔合与运输蛋白Rab6缔合。最后，此处描述了ELKS蛋白家族的一个新成员（人），即ELKS2。 ELKS2的序列（72％氨基酸同一性），IKK激活潜能和相互作用蛋白与ELKS极为相似。 ELKS2可以影响特定的NF-κB靶基因TNFα的表达。两种蛋白质之间的显着差异是它们的组织分布。对该基因家族的进一步研究将为不同组织中IKK和NF-κB转录的调控提供有价值的见解。

著录项

  • 作者

    Ducut Sigala, Jeanette Lourdes.;

  • 作者单位

    University of California, San Diego.;

  • 授予单位 University of California, San Diego.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2004
  • 页码 137 p.
  • 总页数 137
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;
  • 关键词

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