Send to

Choose Destination
Autophagy. 2017;13(11):1981-1994. doi: 10.1080/15548627.2017.1375633. Epub 2017 Sep 29.

Suppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis.

Author information

a Department of Neurology, Tongren Hospital , Shanghai Jiao Tong University School of Medicine (SJTUSM) , Shanghai , China.
b Shanghai Institute of Immunology, Institutes of Medical Sciences , Shanghai Jiao Tong University School of Medicine , Shanghai , China.
c Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & SJTUSM , Shanghai , China.
d Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione Istituto Neurologico "Carlo Besta" , Milan , Italy.
e Department of Biomedical and Pharmaceutical Sciences , Chapman University School of Pharmacy , Irvine , CA , USA.
f Department of Neurology , Fudan University Huashan Hospital, and Institute of Neurology, Fudan University , Shanghai , China.


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.


CHRN, endocytosis; carbonic anhydrase 3; chaperone-assisted selective autophagy; myasthenia gravis

Supplemental Content

Full text links

Icon for Taylor & Francis Icon for PubMed Central
Loading ...
Support Center