Neddylation E1 Obligatory Subunit Nae1 Is Critical to Neuromuscular Junction Development and Maintenance

Rapsyn is a scaffold protein that is thought to anchor acetylcholine receptors at the neuromuscular junction (NMJ). We showed that it may be an E3 ligase that regulates NMJ development by neddylation. To obtain genetical evidence, we mutated Nae1 (APP-BP1), an obligatory subunit of the neddylation E1 enzyme specifically in muscle cells. The mutation decreased the stability of acetylcholine receptor (AChR)α, reduced AChR clustering, and impaired NMJ development in <i>Pax7-Cre;Nae1f/f</i> mice (of either sex) and caused neonatal lethality. Moreover, while NMJs were normal in heterozygous mutant mice of Nae1 or rapsyn C366A (a knock-in mutation that eliminates E3 ligase activity), double heterozygous mutant mice (of either sex) displayed NMJ deficits, indicative of a genetic interaction between Nae1 and rapsyn. These results provide genetic evidence for a role of neddylation in NMJ formation and support the notion that rapsyn serves as a neddylation E3 ligase in NMJ formation.

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Journal
Journal of Neuroscience
Published
2025-07-14
DOI
https://doi.org/10.1523/jneurosci.0098-25.2025
Primary Topic
Muscle Physiology and Disorders
Type
article
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article

Neddylation E1 Obligatory Subunit Nae1 Is Critical to Neuromuscular Junction Development and Maintenance

Minyi Wu, Hongyang Jing, Lin Mei, Lin Dong et al.
Journal of Neuroscience
Muscle Physiology and Disorders
article

Neddylation E1 Obligatory Subunit Nae1 Is Critical to Neuromuscular Junction Development and Maintenance

Minyi Wu, Hongyang Jing, Lin Mei, Lin Dong, Huabo Su, Guanglin Xing, Yu Zheng, Wen‐Cheng Xiong, Peng Chen, Lei Li, Hongsheng Zhang, Hongsheng Wang
article en

Abstract

Rapsyn is a scaffold protein that is thought to anchor acetylcholine receptors at the neuromuscular junction (NMJ). We showed that it may be an E3 ligase that regulates NMJ development by neddylation. To obtain genetical evidence, we mutated Nae1 (APP-BP1), an obligatory subunit of the neddylation E1 enzyme specifically in muscle cells. The mutation decreased the stability of acetylcholine receptor (AChR)α, reduced AChR clustering, and impaired NMJ development in <i>Pax7-Cre;Nae1f/f</i> mice (of either sex) and caused neonatal lethality. Moreover, while NMJs were normal in heterozygous mutant mice of Nae1 or rapsyn C366A (a knock-in mutation that eliminates E3 ligase activity), double heterozygous mutant mice (of either sex) displayed NMJ deficits, indicative of a genetic interaction between Nae1 and rapsyn. These results provide genetic evidence for a role of neddylation in NMJ formation and support the notion that rapsyn serves as a neddylation E3 ligase in NMJ formation.

Journal of NeuroscienceVol. 45(33)
Capital Medical University (CN), Chinese Academy of Sciences (CN), Augusta University (US), Augusta University Health (US), Shanghai Institute of Organic Chemistry (CN), Chinese Institute for Brain Research (CN), China Academy of Chinese Medical Sciences (CN), Case Western Reserve University (US)
Good health and well-being
Openalex Percentile: Top 85%
Muscle Physiology and Disorders
DOIOpen Access PDFOpenAlex
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