重症肌无力
神经肌肉接头
乙酰胆碱受体
生物
骨骼肌
胆碱能的
突触后电位
肌肉无力
内分泌学
细胞生物学
内科学
免疫学
受体
医学
神经科学
生物化学
作者
Ailian Du,Shiqian Huang,Xiaonan Zhao,Kuan Feng,Shuangyan Zhang,Jiefang Huang,Miao Xiang,Fulvio Baggi,Rennolds S. Ostrom,Yanyun Zhang,Xiangjun Chen,Congfeng Xu
出处
期刊:Autophagy
[Informa]
日期:2017-09-29
卷期号:13 (11): 1981-1994
被引量:16
标识
DOI:10.1080/15548627.2017.1375633
摘要
Myasthenia gravis is an autoimmune disorder of the neuromuscular junction manifested as fatigable muscle weakness, which is typically caused by pathogenic autoantibodies against postsynaptic CHRN/AChR (cholinergic receptor nicotinic) in the endplate of skeletal muscle. Our previous studies have identified CA3 (carbonic anhydrase 3) as a specific protein insufficient in skeletal muscle from myasthenia gravis patients. In this study, we investigated the underlying mechanism of how CA3 insufficiency might contribute to myasthenia gravis. Using an experimental autoimmune myasthenia gravis animal model and the skeletal muscle cell C2C12, we find that inhibition of CAR3 (the mouse homolog of CA3) promotes CHRN internalization via a lipid raft-mediated pathway, leading to accelerated degradation of postsynaptic CHRN. Activation of CAR3 reduces CHRN degradation by suppressing receptor endocytosis. CAR3 exerts this effect by suppressing chaperone-assisted selective autophagy via interaction with BAG3 (BCL2-associated athanogene 3) and by dampening endoplasmic reticulum stress. Collectively, our study illustrates that skeletal muscle cell CAR3 is critical for CHRN homeostasis in the neuromuscular junction, and its deficiency leads to accelerated degradation of CHRN and development of myasthenia gravis, potentially revealing a novel therapeutic approach for this disorder.
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