Nature:Orai1突變引發(fā)免疫缺陷

     生物谷報(bào)道：免疫細(xì)胞抗原刺激通過非特異性鈣通透觸發(fā)Ca2+的內(nèi)流,，從而激發(fā)轉(zhuǎn)錄因子NFAT來促進(jìn)機(jī)體對病原體的免疫反應(yīng)。遺傳性免疫缺乏癥患者細(xì)胞缺乏鈣庫調(diào)控性Ca2+內(nèi)流及CRAC通道,。采用SNP和果蠅RNA干擾屏鑒定這些病人的基因缺陷性,發(fā)現(xiàn)一個(gè)含四個(gè)跨膜結(jié)構(gòu)的新蛋白Orai1與該病相關(guān),。SCID患者是ORAI1錯(cuò)義突變純合體，野生型Orai1在SCIDT細(xì)胞中的表達(dá)可恢復(fù)鈣庫調(diào)控性Ca2+內(nèi)流和CRAC的流通,。Orai1是可能是CRAC通道復(fù)合體的組成成分或調(diào)節(jié)物,。

原始出處:A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.

Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. We have previously shown that cells from patients with one form of hereditary severe combined immune deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify the genetic defect in these patients, using a combination of two unbiased genome-wide approaches: a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (ICRAC). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.

友情連接:Orai1突變引發(fā)免疫缺陷