Ni Chang-Yuan, Wu Zhao-Hui, Florence William C, Parekh Vrajesh V, Arrate Maria Pia, Pierce Steven, Schweitzer Brock, Van Kaer Luc, Joyce Sebastian, Miyamoto Shigeki, Ballard Dean W, Oltz Eugene M
Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
J Immunol. 2008 Jun 1;180(11):7107-11. doi: 10.4049/jimmunol.180.11.7107.
Transcription factor NF-kappaB controls the expression of multiple genes involved in immunity and inflammation. The initial activation and duration of NF-kappaB signaling is regulated by posttranslational modifications to IkappaB kinase, which earmarks inhibitors of NF-kappaB for degradation. Prior studies suggest that K63-linked ubiquitination of NEMO (NF-kappaB essential modulator), an IkappaB kinase regulatory subunit, is critical for NF-kappaB and MAPK signaling following engagement of Ag receptors. We now demonstrate that NF-kappaB and MAPK pathways are largely unaffected in primary cells from mice harboring a ubiquitination-defective form of NEMO, NEMO-KR. TLR- but not Ag receptor-induced cellular responses are impaired in NEMO-KR mice, which are more resistant to LPS-induced endotoxic shock than wild-type animals. Thus, one function of NEMO ubiquitination is to fine tune innate immune responses under TLR control.
转录因子NF-κB控制着多个参与免疫和炎症的基因的表达。NF-κB信号传导的初始激活和持续时间由对IκB激酶的翻译后修饰调节，该修饰将NF-κB的抑制剂标记为降解对象。先前的研究表明，IκB激酶调节亚基NEMO（NF-κB必需调节剂）的K63连接的泛素化对于抗原受体参与后的NF-κB和MAPK信号传导至关重要。我们现在证明，在携带泛素化缺陷形式的NEMO（NEMO-KR）的小鼠的原代细胞中，NF-κB和MAPK途径在很大程度上不受影响。在NEMO-KR小鼠中，TLR诱导而非抗原受体诱导的细胞反应受损，这些小鼠比野生型动物对LPS诱导的内毒素休克更具抵抗力。因此，NEMO泛素化的一个功能是在TLR控制下微调先天免疫反应。
