Collagen Q and anti-MuSK autoantibody competitively suppress agrin/LRP4/MuSK signaling.
MuSK antibody-positive myasthenia gravis (MuSK-MG) accounts for 5 to 15% of autoimmune MG. MuSK and LRP4 are coreceptors for agrin in the signaling pathway that causes clustering of acetylcholine receptor (AChR). MuSK also anchors the acetylcholinesterase (AChE)/collagen Q (ColQ) complex to the synaptic basal lamina. We previously reported that anti-MuSK antibodies (MuSK-IgG) block binding of ColQ to MuSK and cause partial endplate AChE deficiency in mice. We here analyzed the physiological significance of binding of ColQ to MuSK and block of this binding by MuSK-IgG. In vitro plate-binding assay showed that MuSK-IgG blocked MuSK-LRP4 interaction in the presence of agrin. Passive transfer of MuSK-IgG to Colq-knockout mice attenuated AChR clustering, indicating that lack of ColQ is not the key event causing defective clustering of AChR in MuSK-MG. In three MuSK-MG patients, the MuSK antibodies recognized the first and fourth immunoglobulin-like domains (Ig1 and Ig4) of MuSK. In two other MuSK-MG patients, they recognized only the Ig4 domain. LRP4 and ColQ also bound to the Ig1 and Ig4 domains of MuSK. Unexpectedly, the AChE/ColQ complex blocked MuSK-LRP4 interaction and suppressed agrin/LRP4/MuSK signaling. Quantitative analysis showed that MuSK-IgG suppressed agrin/LRP4/MuSK signaling to a greater extent than ColQ.
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kenji
K
Otsuka
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Mikako
M
Ito
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Bisei
B
Ohkawara
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Akio
A
Masuda
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Yu
Y
Kawakami
Department of Neurology, Aichi Medical University, Aichi, Japan.
Ko
K
Sahashi
Department of Neurology, Gifu Prefectural General Medical Center, Gifu, Japan.
Hiroshi
H
Nishida
Department of Neurology, Okazaki City Hospital, Okazaki, Japan.
Naoki
N
Mabuchi
Department of Neurology, Meitetsu Hospital, Nagoya, Japan.
Akemi
A
Takano
Department of Neurology, Mayo Clinic, Rochester, Minnesota.
Andrew G
AG
Engel
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Kinji
K
Ohno
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D018171:Agrin / Q000378:metabolism*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D003094:Collagen / Q000235:genetics / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D018171:Agrin; D001323:Autoantibodies; D000939:Epitopes; D007074:Immunoglobulin G; D026502:LDL-Receptor Related Proteins; C551781:LRP4 protein, human; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D011978:Receptors, Nicotinic; D003094:Collagen; C095714:MUSK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000110:Acetylcholinesterase; C114027:COLQ protein, human