Toll-Like Receptor 2 (P631H) Mutant Impairs Membrane Internalization and is a Dominant Negative Allele
Toll-Like Receptor 2 (P631H) Mutant Impairs Membrane Internalization and is a Dominant Negative Allele
复制标题
DOI：
10.1111/j.1365-3083.2010.02379.x
复制
发表时间：
2010-05-01
影响因子：
3.7
通讯作者：
Dembic, Z.
中科院分区：
文献类型：
--
作者：
Etokebe, G. E.;Skjeldal, F.;Dembic, Z.
我们在克罗地亚高加索人群结核病病例对照研究中对208例受试者的416个Toll样受体2（TLR 2）等位基因进行了测序。我们发现了10个单核苷酸多态性（SNP），其中3个是新的（S97 S，T138 I和L266 F）。与接触对照相比，结核病患者中含有TLR 2-P631 H SNP的基因型显著过多，表明疾病风险较小但增加。结核病的病原体是结核分枝杆菌，其可以与具有脂蛋白外壳的TLR 2结合。在转染的HEK 293肾细胞中，TLR 2-P631 H突变体对野生型TLR 2信号传导具有显性负效应，其使用NF-κ B驱动的荧光素酶作为具有配体如M的报告基因。鸟提取物，分别结合TLR 2/TLR 1或TLR 2/TLR 6异二聚体的Pam 3CysSK 4或FSL-1。从Regular Madine达比犬肾细胞表面内化至早期内体隔室的研究显示，与野生型相比，突变体的发生率较低。我们的数据，结合其他人的报告表明，TLR 2-P631 H等位基因可能与脑膜炎球菌脑膜炎的保护，表明通过显性抑制细胞的反应，在免疫反应中重要的突变体可能赋予保护或易感性脑膜炎或结核病，分别。
We have sequenced 416 Toll-like receptor-2 (TLR2) alleles in 208 subjects in a tuberculosis case-control study in Croatian Caucasian population. We found ten single nucleotide polymorphisms (SNP) among which three were novel (S97S, T138I and L266F). The genotype containing TLR2-P631H SNP was significantly overrepresented in patients with tuberculosis when compared to contact controls, suggesting a small yet increased risk to disease. The causative agent of tuberculosis is Mycobacterium tuberculosis, which can bind to TLR2 with its lipoprotein coat. The TLR2-P631H mutant has a dominant negative effect on the wild type TLR2 signalling in transfected HEK293 kidney cells using the NF-kappa B-driven luciferase as a reporter gene with ligands like M. avium extracts, Pam3CysSK4 or FSL-1 that bind TLR2/TLR1 or TLR2/TLR6 heterodimers, respectively. Studies on internalization from the Regular Madine Darby Canine Kidney cell surface into the early endosomal compartments showed a lower rate of the mutant compared to the wild type. Our data, in combination with a report by others show that the TLR2-P631H allele could be associated with protection to meningococcal meningitis, suggest that by dominantly inhibiting the response of cells important in the immune response this mutant might confer either protection or susceptibility to meningitis or tuberculosis, respectively.