Ramachandran Kapil V, Margolis Seth S
Department of Biological Chemistry, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Solomon H. Snyder Department of Neuroscience, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nat Struct Mol Biol. 2017 Apr;24(4):419-430. doi: 10.1038/nsmb.3389. Epub 2017 Mar 13.
In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It is unclear how proteasomes are able to acutely regulate such processes, as this action is inconsistent with their canonical role in proteostasis. Here we describe a mammalian nervous-system-specific membrane proteasome complex that directly and rapidly modulates neuronal function by degrading intracellular proteins into extracellular peptides that can stimulate neuronal signaling. This proteasome complex is closely associated with neuronal plasma membranes, exposed to the extracellular space, and catalytically active. Selective inhibition of the membrane proteasome complex by a cell-impermeable proteasome inhibitor blocked the production of extracellular peptides and attenuated neuronal-activity-induced calcium signaling. Moreover, we observed that membrane-proteasome-derived peptides were sufficient to induce neuronal calcium signaling. Our discoveries challenge the prevailing notion that proteasomes function primarily to maintain proteostasis, and highlight a form of neuronal communication that takes place through a membrane proteasome complex.
在神经系统中，诸如神经元传递和钙信号传导等快速发生的过程会受到蛋白酶体功能短期抑制的影响。目前尚不清楚蛋白酶体如何能够急性调节这些过程，因为这种作用与其在蛋白质稳态中的经典作用不一致。在这里，我们描述了一种哺乳动物神经系统特异性膜蛋白酶体复合物，它通过将细胞内蛋白质降解为可刺激神经元信号传导的细胞外肽，直接且快速地调节神经元功能。这种蛋白酶体复合物与神经元质膜紧密相关，暴露于细胞外空间，且具有催化活性。一种细胞不可渗透的蛋白酶体抑制剂对膜蛋白酶体复合物的选择性抑制阻断了细胞外肽的产生，并减弱了神经元活动诱导的钙信号传导。此外，我们观察到膜蛋白酶体衍生的肽足以诱导神经元钙信号传导。我们的发现挑战了蛋白酶体主要功能是维持蛋白质稳态的普遍观念，并突出了一种通过膜蛋白酶体复合物发生的神经元通讯形式。
