Impact of polymorphisms in the DC-SIGNR neck domain on the interaction with pathogens.
Impact of polymorphisms in the DC-SIGNR neck domain on the interaction with pathogens.
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DOI：
10.1016/j.virol.2005.11.033
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发表时间：
2006-04-10
期刊：
影响因子：
3.7
通讯作者：
Pöhlmann S
中科院分区：
文献类型：
--
作者：
Gramberg T;Zhu T;Chaipan C;Marzi A;Liu H;Wegele A;Andrus T;Hofmann H;Pöhlmann S
凝集素DC-SIGN和DC-SIGNR增强人类免疫缺陷病毒（HIV）、埃博拉病毒（EBOV）和其他病原体的感染。这些蛋白质的颈域驱动多聚化，这被认为是有效识别多价配体所需的。DC-SIGN的颈部结构域由7个具有罕见变异的序列重复组成。相比之下，DC-SIGNR颈部结构域是多态性的，并且除了具有7个重复单元的野生型（wt）等位基因之外，经常发现具有5个和6个序列重复的等位基因形式。因此，我们研究了具有五个和六个重复单元的DC-SIGNR等位基因是否表现出病原体捕获缺陷。在这里，我们表明，野生型DC-SIGNR和患者来源的等位基因与五个和六个重复结合病毒糖蛋白，增强病毒感染和四聚体具有可比的效率。此外，与每个等位基因单独表达相比，wt DC-SIGNR和具有五个重复的等位基因的共表达没有减少与病原体的相互作用，这表明至少在高表达条件下，异源寡聚体的潜在形成没有明显减少病原体结合。因此，我们的研究结果并没有提供证据减少病原体捕获的DC-SIGNR等位基因与五个和六个重复单位。尽管我们不能排除这种微妙的，但体内相关的差异仍未被检测到，我们的分析表明，间接机制可以解释DC-SIGNR颈部区域多态性与HIV-1感染风险降低的相关性。
The lectins DC-SIGN and DC-SIGNR augment infection by human immunodeficiency virus (HIV), Ebolavirus (EBOV) and other pathogens. The neck domain of these proteins drives multimerization, which is believed to be required for efficient recognition of multivalent ligands. The neck domain of DC-SIGN consists of seven sequence repeats with rare variations. In contrast, the DC-SIGNR neck domain is polymorphic and, in addition to the wild type (wt) allele with seven repeat units, allelic forms with five and six sequence repeats are frequently found. A potential association of the DC-SIGNR genotype and risk of HIV-1 infection is currently under debate. Therefore, we investigated if DC-SIGNR alleles with five and six repeat units exhibit defects in pathogen capture. Here, we show that wt DC-SIGNR and patient derived alleles with five and six repeats bind viral glycoproteins, augment viral infection and tetramerize with comparable efficiency. Moreover, coexpression of wt DC-SIGNR and alleles with five repeats did not decrease the interaction with pathogens compared to expression of each allele alone, suggesting that potential formation of hetero-oligomers does not appreciably reduce pathogen binding, at least under conditions of high expression. Thus, our results do not provide evidence for diminished pathogen capture by DC-SIGNR alleles with five and six repeat units. Albeit, we cannot exclude that subtle, but in vivo relevant differences remained undetected, our analysis suggests that indirect mechanisms could account for the association of polymorphisms in the DC-SIGNR neck region with reduced risk of HIV-1 infection.
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