Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly.
Two human MYD88 variants, S34Y and R98C, interfere with MyD88-IRAK4-myddosome assembly.
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DOI：
10.1074/jbc.m110.159996
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发表时间：
2011-01-14
期刊：
影响因子：
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通讯作者：
Weber AN
中科院分区：
文献类型：
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作者：
George J;Motshwene PG;Wang H;Kubarenko AV;Rautanen A;Mills TC;Hill AV;Gay NJ;Weber AN
先天免疫受体检测微生物病原体，随后激活适应性免疫反应来对抗病原体的入侵。MyD88是toll样受体（TLR）和IL-1受体超家族信号通路中的关键衔接分子。携带罕见的，自然发生的MYD88点突变的人类个体遭受反复发生的危及生命的感染的事实说明了这一点。在这里，我们分析了六个报道的MYD88在体外细胞系统中的非同义单核苷酸多态性的功能特性。在MyD88死亡结构域中发现的两个变异，S34Y和R98C，由于同源寡聚化和IRAK4相互作用的减少，NF-κB活化严重降低。结构建模强调Ser-34和Arg-98是Myddosome组装的重要残基，Myddosome是一种死亡结构域（DD）受体后复合体，涉及MyD88、IRAK4、IRAK2或IRAK1的DD。使用S34Y和R98C作为功能探针，我们的数据显示MyD88同源寡聚和IRAK4相互作用是由MyD88 TIR和IRAK4激酶结构域调节的，证明了在最近的Myddosome晶体结构中未观察到的非dd区域的功能重要性。S34Y和R98C对部分（IL-1受体、TLR2、TLR4、TLR5和TLR7）但不是全部（TLR9） myd88依赖性信号通路的差异干扰也表明受体特异性存在于Myddosome水平。考虑到它们对信号传导的有害影响，我们在几个病例对照研究中的流行病学分析证实，S34Y和R98C是罕见的变异，可能仅在少数个体中对感染易感性有很大贡献，这并不奇怪。
Innate immune receptors detect microbial pathogens and subsequently activate adaptive immune responses to combat pathogen invasion. MyD88 is a key adaptor molecule in both Toll-like receptor (TLR) and IL-1 receptor superfamily signaling pathways. This is illustrated by the fact that human individuals carrying rare, naturally occurring MYD88 point mutations suffer from reoccurring life-threatening infections. Here we analyzed the functional properties of six reported non-synonymous single nucleotide polymorphisms of MYD88 in an in vitro cellular system. Two variants found in the MyD88 death domain, S34Y and R98C, showed severely reduced NF-κB activation due to reduced homo-oligomerization and IRAK4 interaction. Structural modeling highlights Ser-34 and Arg-98 as residues important for the assembly of the Myddosome, a death domain (DD) post-receptor complex involving the DD of MyD88, IRAK4, and IRAK2 or IRAK1. Using S34Y and R98C as functional probes, our data show that MyD88 homo-oligomerization and IRAK4 interaction is modulated by the MyD88 TIR and IRAK4 kinase domain, demonstrating the functional importance of non-DD regions not observed in a recent Myddosome crystal structure. The differential interference of S34Y and R98C with some (IL-1 receptor, TLR2, TLR4, TLR5, and TLR7) but not all (TLR9) MyD88-dependent signaling pathways also suggests that receptor specificities exist at the level of the Myddosome. Given their detrimental effect on signaling, it is not surprising that our epidemiological analysis in several case-control studies confirms that S34Y and R98C are rare variants that may drastically contribute to susceptibility to infection in only few individuals.