Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK
Genetic and physical interaction of the B-cell systemic lupus erythematosus-associated genes BANK1 and BLK
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DOI：
10.1136/annrheumdis-2011-200085
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发表时间：
2012-01-01
影响因子：
27.4
通讯作者：
Alarcon-Riquelme, Marta E.
中科院分区：
文献类型：
--
作者：
Castillejo-Lopez, Casimiro;Delgado-Vega, Angelica M.;Alarcon-Riquelme, Marta E.
目的系统性红斑狼疮（SLE）患者B细胞信号转导异常是其主要特征。BANK 1和BLK基因最近被描述为与SLE相关。BANK 1编码参与B细胞受体信号传导的B细胞特异性胞质蛋白，BLK编码在B细胞发育中具有重要作用的Src酪氨酸激酶。为探讨BANK 1和BLK在SLE发病中的作用，采用遗传交互作用分析方法，研究BANK 1和BLK基因间的交互作用。方法采用GPAT 16方法分析BANK 1和BLK基因间的交互作用。共聚焦显微镜被用来调查共定位，和免疫沉淀被用来验证BANK 1和BLK.Results与SLE相关的BANK 1和BLK多态性之间的物理相互作用的上位相互作用观察到的发现集279例患者和515个控制从北方欧洲。对4399名欧洲人的荟萃分析证实了BANK 1和BLK之间的遗传相互作用。由于BANK 1被鉴定为Src酪氨酸激酶林恩的结合配偶体，因此测试了BANK 1和BLK也可以显示蛋白质-蛋白质相互作用的可能性。证明了BLK和BANK 1的共免疫沉淀和共定位。在Daudi细胞系和初级幼稚B细胞的内源性结合增强后，B细胞受体的刺激，使用抗IgM antibodies.Conclusions本研究表明BANK 1和BLK之间的遗传相互作用，并表明这些分子相互作用的物理。这些结果对于了解SLE和其他自身免疫性疾病具有重要意义，并确定了一种潜在的新信号通路。
Objectives Altered signalling in B cells is a predominant feature of systemic lupus erythematosus (SLE). The genes BANK1 and BLK were recently described as associated with SLE. BANK1 codes for a B-cell-specific cytoplasmic protein involved in B-cell receptor signalling and BLK codes for an Src tyrosine kinase with important roles in B-cell development. To characterise the role of BANK1 and BLK in SLE, a genetic interaction analysis was performed hypothesising that genetic interactions could reveal functional pathways relevant to disease pathogenesis.Methods The GPAT16 method was used to analyse the gene-gene interactions of BANK1 and BLK. Confocal microscopy was used to investigate co-localisation, and immunoprecipitation was used to verify the physical interaction of BANK1 and BLK.Results Epistatic interactions between BANK1 and BLK polymorphisms associated with SLE were observed in a discovery set of 279 patients and 515 controls from northern Europe. A meta-analysis with 4399 European individuals confirmed the genetic interactions between BANK1 and BLK. As BANK1 was identified as a binding partner of the Src tyrosine kinase LYN, the possibility that BANK1 and BLK could also show a protein-protein interaction was tested. The co-immunoprecipitation and co-localisation of BLK and BANK1 were demonstrated. In a Daudi cell line and primary naive B cells endogenous binding was enhanced upon B-cell receptor stimulation using anti-IgM antibodies.Conclusions This study shows a genetic interaction between BANK1 and BLK, and demonstrates that these molecules interact physically. The results have important consequences for the understanding of SLE and other autoimmune diseases and identify a potential new signalling pathway.