Suppression of CHRN Endocytosis by Carbonic Anhydrase CAR3 in the Pathogenesis of Myasthenia Gravis

Authors

Ailian Du, Shanghai Jiao Tong University
Shiqian Huang, Shanghai Jiao Tong University
Xiaonan Zhao, Shanghai Jiao Tong University
Kuan Fang, Chinese Academy of Sciences
Shuangyan Zhang, Shanghai Jiao Tong University
Jiefang Huang, Chinese Academy of Sciences
Xiang Miao, Chinese Academy of Sciences
Fulvio Baggi, Fondazione Istituto Neurologico “Carlo Besta”
Rennolds S. Ostrom, Chapman UniversityFollow
Yanyun Zhang, Shanghai Jiao Tong University
Xiangjun Chen, Fudan University Huashan Hospital
Congfeng Xu, Shanghai Jiao Tong University

Document Type

Article

Publication Date

9-21-2017

Abstract

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.

Comments

This article was originally published in Autophagy, volume 13, issue 11, in 2017. DOI: 10.1080/15548627.2017.1375633

Recommended Citation

Du A, Huang S, Zhao X, et al. Suppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis. Autophagy. 2017;13(11):1981-1994. doi: 10.1080/15548627.2017.1375633

Copyright

The authors

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