Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development.
Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development.
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大脑发育过程中 UBE4B-KLHL22 E3 泛素连接酶级联对 mTOR 信号传导的微调
DOI：
10.1242/dev.201286
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发表时间：
2022-12-15
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影响因子：
--
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雷帕霉素（mTOR）通路机制靶点的时空调控对脑结构的建立至关重要。mTOR信号的失调与多种神经发育障碍有关。在这里，我们证明了UBE4B-KLHL22 E3泛素连接酶级联调节神经发育中的mTOR活性。在神经系统中有条件地缺失UBE4B的小鼠模型中，动物表现出严重的生长缺陷、自发性癫痫发作和过早死亡。突变小鼠大脑中UBE4B的缺失导致神经前体细胞的消耗和神经发生的损害。在机制上，UBE4B多泛素化并降解KLHL22，这是一种E3连接酶，先前被证明可以降解GATOR1组分DEPDC5。UBE4B缺失导致KLHL22上调，mTOR过度激活，导致神经前体细胞增殖分化缺陷。KLHL22表达的抑制逆转了UBE4B急性局部缺失引起的mTOR活性升高。产前用mTOR抑制剂雷帕霉素治疗Ube4b突变小鼠的神经发生缺陷综上所述，这些发现表明UBE4B和KLHL22通过微调mTOR活性对前体池的维持和分化至关重要。UBE4B-KLHL22 E3级联严格控制mTOR信号的激活，并在小鼠大脑发育过程中维持适当水平的围产期神经发生。
Spatiotemporal regulation of the mechanistic target of rapamycin (mTOR) pathway is pivotal for establishment of brain architecture. Dysregulation of mTOR signaling is associated with a variety of neurodevelopmental disorders. Here, we demonstrate that the UBE4B-KLHL22 E3 ubiquitin ligase cascade regulates mTOR activity in neurodevelopment. In a mouse model with UBE4B conditionally deleted in the nervous system, animals display severe growth defects, spontaneous seizures and premature death. Loss of UBE4B in the brains of mutant mice results in depletion of neural precursor cells and impairment of neurogenesis. Mechanistically, UBE4B polyubiquitylates and degrades KLHL22, an E3 ligase previously shown to degrade the GATOR1 component DEPDC5. Deletion of UBE4B causes upregulation of KLHL22 and hyperactivation of mTOR, leading to defective proliferation and differentiation of neural precursor cells. Suppression of KLHL22 expression reverses the elevated activity of mTOR caused by acute local deletion of UBE4B. Prenatal treatment with the mTOR inhibitor rapamycin rescues neurogenesis defects in Ube4b mutant mice. Taken together, these findings demonstrate that UBE4B and KLHL22 are essential for maintenance and differentiation of the precursor pool through fine-tuning of mTOR activity. The UBE4B-KLHL22 E3 cascade tightly controls activation of mTOR signaling and sustains perinatal neurogenesis at an appropriate level during mouse brain development.
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