Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Northwestern University, Center for Autism and Neurodevelopment, Chicago, IL 60611, USA.
Cell Rep. 2020 May 26;31(8):107685. doi: 10.1016/j.celrep.2020.107685.
Signaling by the cytokine transforming growth factor β (TGF-β) has been implicated in a multitude of biological functions; however, TGF-β signaling, particularly in the CNS, remains largely unexplored. ANK3 variants (encoding ankyrin-G) are associated with bipolar disorder, intellectual disability, and autism spectrum disorder, while mutations in USP9X, which encodes a deubiquitinase, are associated with X-linked intellectual disability and autism in humans. Here, we show that TGF-β signaling promotes Usp9X phosphorylation, which enhances its interaction with ankyrin-G and stabilizes ankyrin-G in spines, leading to spine enlargement. Using in situ proximity ligation combined with structured illumination superresolution microscopy, we characterize the postsynaptic spatial organization of phosphorylation-dependent regulation of Usp9X/ankyrin-G interactions in dendrites and its quantitative relationship with spine morphology and number. These data reveal a cytokine-mediated mechanism regulating protein stability in spines and suggest a role for deubiquitination and TGF-β signaling in neurodevelopmental disorder pathogenesis and treatment.
细胞因子转化生长因子 β (TGF-β) 的信号转导与多种生物学功能有关；然而，TGF-β信号转导，特别是在中枢神经系统中，仍然在很大程度上未被探索。ANK3 变体（编码锚蛋白-G）与双相情感障碍、智力障碍和自闭症谱系障碍有关，而编码去泛素化酶的 USP9X 突变与人类 X 连锁智力障碍和自闭症有关。在这里，我们表明 TGF-β 信号转导促进 Usp9X 的磷酸化，从而增强其与锚蛋白-G 的相互作用，并稳定棘突中的锚蛋白-G，导致棘突增大。通过原位邻近连接结合结构照明显微镜，我们描述了 Usp9X/ankyrin-G 相互作用在树突中的磷酸化依赖性调节的突触后空间组织及其与棘突形态和数量的定量关系。这些数据揭示了一种细胞因子介导的调节棘突中蛋白质稳定性的机制，并提示去泛素化和 TGF-β 信号转导在神经发育障碍发病机制和治疗中的作用。
