Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling.
Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling.
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DOI：
10.1038/srep13928
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发表时间：
2015-09-10
影响因子：
4.6
通讯作者：
Ohno K
中科院分区：
文献类型：
--
作者：
Otsuka K;Ito M;Ohkawara B;Masuda A;Kawakami Y;Sahashi K;Nishida H;Mabuchi N;Takano A;Engel AG;Ohno K
MuSK抗体阳性重症肌无力（MuSK-MG）占自身免疫性MG的5 - 15%。MuSK和LRP 4是聚集蛋白的共受体，在引起乙酰胆碱受体（AChR）聚集的信号通路中。MuSK还将乙酰胆碱酯酶（AChE）/胶原蛋白Q（ColQ）复合物锚定到突触基底层。我们以前报道过，抗MuSK抗体（MuSK-IgG）阻断ColQ与MuSK的结合，并导致小鼠终板AChE部分缺陷。我们在此分析了ColQ与MuSK结合的生理意义以及MuSK-IgG对这种结合的阻断。体外平板结合试验表明，在聚集蛋白存在下，MuSK-IgG阻断MuSK-LRP 4相互作用。将MuSK-IgG被动转移到Colq敲除小鼠中会减弱AChR聚集，这表明缺乏ColQ并不是导致MuSK-MG中AChR聚集缺陷的关键事件。在3例MuSK-MG患者中，MuSK抗体识别MuSK的第一和第四免疫球蛋白样结构域（Ig 1和Ig 4）。在另外两名MuSK-MG患者中，他们仅识别Ig 4结构域。LRP 4和ColQ也结合MuSK的Ig 1和Ig 4结构域。出乎意料的是，AChE/ColQ复合物阻断了MuSK-LRP 4相互作用并抑制了聚集蛋白/LRP 4/MuSK信号传导。定量分析显示MuSK-IgG抑制聚集蛋白/LRP 4/MuSK信号传导的程度大于ColQ。
MuSK antibody-positive myasthenia gravis (MuSK-MG) accounts for 5 to 15% of autoimmune MG. MuSK and LRP4 are coreceptors for agrin in the signaling pathway that causes clustering of acetylcholine receptor (AChR). MuSK also anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. We previously reported that anti-MuSK antibodies (MuSK-IgG) block binding of ColQ to MuSK and cause partial endplate AChE deficiency in mice. We here analyzed the physiological significance of binding of ColQ to MuSK and block of this binding by MuSK-IgG. In vitro plate-binding assay showed that MuSK-IgG blocked MuSK-LRP4 interaction in the presence of agrin. Passive transfer of MuSK-IgG to Colq-knockout mice attenuated AChR clustering, indicating that lack of ColQ is not the key event causing defective clustering of AChR in MuSK-MG. In three MuSK-MG patients, the MuSK antibodies recognized the first and fourth immunoglobulin-like domains (Ig1 and Ig4) of MuSK. In two other MuSK-MG patients, they recognized only the Ig4 domain. LRP4 and ColQ also bound to the Ig1 and Ig4 domains of MuSK. Unexpectedly, the AChE/ColQ complex blocked MuSK-LRP4 interaction and suppressed agrin/LRP4/MuSK signaling. Quantitative analysis showed that MuSK-IgG suppressed agrin/LRP4/MuSK signaling to a greater extent than ColQ.