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

Journal of molecular medicine (Berlin, Germany) 2021 Dec

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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. © 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Citation

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. Hyper-SUMOylation of SMN induced by SENP2 deficiency decreases its stability and leads to spinal muscular atrophy-like pathology. Journal of molecular medicine (Berlin, Germany). 2021 Dec;99(12):1797-1813