Abstract
Neurogenesis plays a critical role in brain physiology and behavioral performance, and defective neurogenesis leads to neurological and psychiatric disorders. Here, we show that PLCβ4 expression is markedly reduced in SENP2-deficient cells and mice, resulting in decreased IP3 formation and altered intracellular calcium homeostasis. PLCβ4 stability is regulated by the SUMO-dependent ubiquitin-mediated proteolytic pathway, which is catalyzed by PIAS2α and RNF4. SUMOylated PLCβ4 is transported to the nucleus through Nup205- and RanBP2-dependent pathways and regulates nuclear signaling. Furthermore, dysregulated calcium homeostasis induced defects in neurogenesis and neuronal viability in SENP2-deficient mice. Finally, SENP2 and PLCβ4 are stimulated by starvation and oxidative stress, which maintain calcium homeostasis regulated neurogenesis. Our findings provide mechanistic insight into the critical roles of SENP2 in the regulation of PLCβ4 SUMOylation, and the involvement of SENP2-PLCβ4 axis in calcium homeostasis regulated neurogenesis under stress.
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Acknowledgements
We are grateful to Dr. Richard Vallee from Columbia University for kindly providing the sh-RanBP2 plasmid, and we also thank Dr. Xing Li from Shaanxi Normal University for their technical supports and Dr. Yingfang Tian from Shaanxi Normal University for critical reading of the paper.
Funding
This study was supported by grants from the National Natural Science Foundation of China (81671294 and 81870241 to YTQ), and the Fundamental Research Funds for the Central Universities (GK201903066 to HMW).
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XC, HMW, and YTQ conceptualized and designed the research. XC, YYQ, and YHZ developed experimental methods, performed most experiments and analyzed the data. XYY, ZCX, YJS, and JKC provided technical supports. HMW and YTQ supervised the study. XC, HMW, and YTQ wrote the paper with editorial input from ETHY. All authors have read and approved the paper.
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All animal care and studies were performed according to protocols “Guide for the Care and Use of Laboratory Animals”, which were approved by the Institutional Animal Care and Use Committee at Shaanxi Normal University, and all manipulations were conducted in consistence with established guidelines.
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Chen, X., Qin, Y., Zhang, Y. et al. SENP2-PLCβ4 signaling regulates neurogenesis through the maintenance of calcium homeostasis. Cell Death Differ 29, 337–350 (2022). https://doi.org/10.1038/s41418-021-00857-1
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DOI: https://doi.org/10.1038/s41418-021-00857-1
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