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Hyper-SUMOylation of SMN induced by SENP2 deficiency decreases its stability and leads to spinal muscular atrophy-like pathology

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Abstract

Spinal muscular atrophy (SMA), a degenerative motor neuron disease and a leading cause of infant mortality, is caused by loss of functional survival motor neuron (SMN) protein due to SMN1 gene mutation. Here, using mouse and cell models for behavioral and histological studies, we found that SENP2 (SUMO/sentrin-specific protease 2)-deficient mice developed a notable SMA-like pathology phenotype with significantly decreased muscle fibers and motor neurons. At the molecular level, SENP2 deficiency in mice did not affect transcription but decreased SMN protein levels by promoting the SUMOylation of SMN. SMN was modified by SUMO2 with the E3 PIAS2α and deconjugated by SENP2. SUMOylation of SMN accelerated its degradation by the ubiquitin–proteasome degradation pathway with the ubiquitin E1 UBA1 (ubiquitin-like modifier activating enzyme 1) and E3 ITCH. SUMOylation of SMN increased its acetylation to inhibit the formation of Cajal bodies (CBs). These results showed that SENP2 deficiency induced hyper-SUMOylation of the SMN protein, which further affected the stability and functions of the SMN protein, eventually leading to the SMA-like phenotype. Thus, we uncovered the important roles for hyper-SUMOylation of SMN induced by SENP2 deficiency in motor neurons and provided a novel targeted therapeutic strategy for SMA.

Key messages

  • SENP2 deficiency enhanced the hyper-SUMOylation of SMN and promoted the degradation of SMN by the ubiquitin–proteasome pathway.

  • SUMOylation increased the acetylation of SMN to inhibit CB formation.

  • SENP2 deficiency caused hyper-SUMOylation of SMN protein, which further affected the stability and functions of SMN protein and eventually led to the occurrence of SMA-like pathology.

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Data availability

All the authors declare that data and materials are available upon request.

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Funding

This research was funded by the National Natural Science Foundation of China (81671294 and 81870241 to YTQ) and the Fundamental Research Funds for the Central Universities (GK201903066 to HW).

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  1. Yuhong Zhang, Xu Chen, Qiqi Wang have contributed equally to the work.

Authors and Affiliations

  1. Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, 710119, Shaanxi, China

    Yuhong Zhang, Xu Chen, Qiqi Wang, Congcong Du, Wenbin Lu, Hong Yuan, Zhenzhen Zhang, Danqing Li, Xing Ling, Xiang Ren, Yang Zhao, Qi Su, Zhengcao Xing, Yuanyuan Qin, Xinyi Yang, Yajie Shen, Hongmei Wu & Yitao Qi

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  1. Yuhong Zhang
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Contributions

Y.H.Z. maintained the mice and identified the SMA-like phenotype; Y.H.Z., X.C., Q.Q.W., and Q.S. performed SUMOylation, ubiquitination, and acetylation analysis; Y.Y.Q., C.C.D., and D.Q.L. determined the SUMO sites of SMN; X.Y.Y., W.B.L., and X.L. performed the analysis of SMN1 transcript levels; Z.C.X., H.Y., and X.R. conducted the analysis of SMN protein levels; Y.J.S., Z.Z.Z., and Y.Z. conducted the Gemin2 experiments; H.M.W. and Y.T.Q. conceived the project; H.M.W. and Y.T.Q. wrote the paper with editorial input from Y.H.Z. and X.C.

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Correspondence to Hongmei Wu or Yitao Qi.

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All animal care procedures and studies were performed according to protocols approved by the Institutional Animal Care and Use Committee of Shaanxi Normal University, Xi’an, China.

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Zhang, Y., Chen, X., Wang, Q. et al. Hyper-SUMOylation of SMN induced by SENP2 deficiency decreases its stability and leads to spinal muscular atrophy-like pathology. J Mol Med 99, 1797–1813 (2021). https://doi.org/10.1007/s00109-021-02130-x

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