TY - JOUR
T1 - Suppression of CHRN endocytosis by carbonic anhydrase CAR3 in the pathogenesis of myasthenia gravis
AU - Du, Ailian
AU - Huang, Shiqian
AU - Zhao, Xiaonan
AU - Feng, Kuan
AU - Zhang, Shuangyan
AU - Huang, Jiefang
AU - Miao, Xiang
AU - Baggi, Fulvio
AU - Ostrom, Rennolds S.
AU - Zhang, Yanyun
AU - Chen, Xiangjun
AU - Xu, Congfeng
PY - 2017/11/2
Y1 - 2017/11/2
N2 - 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.
AB - 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.
KW - carbonic anhydrase 3
KW - chaperone-assisted selective autophagy
KW - CHRN, endocytosis
KW - myasthenia gravis
UR - http://www.scopus.com/inward/record.url?scp=85030159820&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85030159820&partnerID=8YFLogxK
U2 - 10.1080/15548627.2017.1375633
DO - 10.1080/15548627.2017.1375633
M3 - Article
AN - SCOPUS:85030159820
VL - 13
SP - 1981
EP - 1994
JO - Autophagy
JF - Autophagy
SN - 1554-8627
IS - 11
ER -