Sorting nexin 17 increases low-density lipoprotein receptor-related protein 4 membrane expression: A novel mechanism of acetylcholine receptor aggregation in myasthenia gravis

Xiaoxiao He; Xiaoxiao He; Shuxian Zhou; Shuxian Zhou; Ying Ji; Ying Ji; Yingna Zhang; Jie Lv; Shangkun Quan; Jing Zhang; Xue Zhao; Weike Cui; Weike Cui; Wenbo Li; Wenbo Li; Peipei Liu; Peipei Liu; Linyuan Zhang; Linyuan Zhang; Tong Shen; Hua Fang; Junhong Yang; Yunke Zhang; Xinzheng Cui; Qingyong Zhang; Feng Gao

doi:10.3389/fimmu.2022.916098

Frontiers in Immunology (Oct 2022)

Sorting nexin 17 increases low-density lipoprotein receptor-related protein 4 membrane expression: A novel mechanism of acetylcholine receptor aggregation in myasthenia gravis

Xiaoxiao He,
Xiaoxiao He,
Shuxian Zhou,
Shuxian Zhou,
Ying Ji,
Ying Ji,
Yingna Zhang,
Jie Lv,
Shangkun Quan,
Jing Zhang,
Xue Zhao,
Weike Cui,
Weike Cui,
Wenbo Li,
Wenbo Li,
Peipei Liu,
Peipei Liu,
Linyuan Zhang,
Linyuan Zhang,
Tong Shen,
Hua Fang,
Junhong Yang,
Yunke Zhang,
Xinzheng Cui,
Qingyong Zhang,
Feng Gao

Affiliations

Xiaoxiao He: BGI College, Zhengzhou University, Zhengzhou, China
Xiaoxiao He: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Shuxian Zhou: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Shuxian Zhou: Basic Medical College, Zhengzhou University, Zhengzhou, China
Ying Ji: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Ying Ji: Department of Neurology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Yingna Zhang: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Jie Lv: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Shangkun Quan: Department of Pathophysiology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
Jing Zhang: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Xue Zhao: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Weike Cui: BGI College, Zhengzhou University, Zhengzhou, China
Weike Cui: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Wenbo Li: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Wenbo Li: Department of Neurology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Peipei Liu: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Peipei Liu: Basic Medical College, Zhengzhou University, Zhengzhou, China
Linyuan Zhang: BGI College, Zhengzhou University, Zhengzhou, China
Linyuan Zhang: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Tong Shen: Department of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
Hua Fang: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
Junhong Yang: Department of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
Yunke Zhang: Department of Encephalopathy, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China
Xinzheng Cui: Myasthenia Gravis Comprehensive Diagnosis and Treatment Center, Henan Provincial People’s Hospital, Zhengzhou, China
Qingyong Zhang: Myasthenia Gravis Comprehensive Diagnosis and Treatment Center, Henan Provincial People’s Hospital, Zhengzhou, China
Feng Gao: Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China

DOI: https://doi.org/10.3389/fimmu.2022.916098
Journal volume & issue: Vol. 13

Abstract

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Myasthenia gravis (MG) is characterized by autoimmune damage to the postsynaptic membrane of the neuromuscular junction (NMJ) with impaired postsynaptic acetylcholine receptor (AChR) aggregation. Low-density lipoprotein receptor-related protein 4 (LRP4) plays an important role in AChR aggregation at endplate membranes via the Agrin–LRP4–muscle-specific receptor tyrosine kinase (MuSK) cascade. Sorting nexin 17 (SNX17) regulates the degradation and recycling of various internalized membrane proteins. However, whether SNX17 regulates LRP4 remains unclear. Therefore, we examined the regulatory effects of SNX17 on LRP4 and its influence on AChR aggregation in MG. We selected C2C12 myotubes and induced LRP4 internalization via stimulation with anti-LRP4 antibody and confirmed intracellular interaction between SNX17 and LRP4. SNX17 knockdown and overexpression confirmed that SNX17 promoted MuSK phosphorylation and AChR aggregation by increasing cell surface LRP4 expression. By establishing experimental autoimmune MG (EAMG) mouse models, we identified that SNX17 upregulation improved fragmentation of the AChR structure at the NMJ and alleviated leg weakness in EAMG mice. Thus, these results reveal that SNX17 may be a novel target for future MG therapy.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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