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.

神经发生在大脑生理和行为表现中起着至关重要的作用，有缺陷的神经发生会导致神经和精神疾病。在这里，我们显示 PLCβ4 表达在 SENP2 缺陷细胞和小鼠中显着降低，导致 IP _3降低形成和改变细胞内钙稳态。PLCβ4 的稳定性受到 SUMO 依赖性泛素介导的蛋白水解途径的调节，该途径由 PIAS2α 和 RNF4 催化。SUMOylated PLCβ4 通过 Nup205 和 RanBP2 依赖性途径转运至细胞核并调节核信号传导。此外，失调的钙稳态会导致 SENP2 缺陷小鼠的神经发生和神经元活力缺陷。最后，SENP2 和 PLCβ4 受到饥饿和氧化应激的刺激，从而维持钙稳态调节的神经发生。我们的研究结果提供了对 SENP2 在调节 PLCβ4 SUMOylation 中的关键作用的机制洞察，以及 SENP2-PLCβ4 轴参与钙稳态调节应激下的神经发生。