Latent C termini–specificity links the E3 ubiquitin ligase CHIP to caspases.
Specificity for latent C termini links the E3 ubiquitin ligase CHIP to caspases.
机构信息
Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA, USA.
Department of Neurology, Memory and Aging Center, University of California at San Francisco, San Francisco, CA, USA.
出版信息
Nat Chem Biol. 2019 Aug;15(8):786-794. doi: 10.1038/s41589-019-0322-6. Epub 2019 Jul 18.
Protein-protein interactions between E3 ubiquitin ligases and protein termini help shape the proteome. These interactions are sensitive to proteolysis, which alters the ensemble of cellular N and C termini. Here we describe a mechanism wherein caspase activity reveals latent C termini that are then recognized by the E3 ubiquitin ligase CHIP. Using expanded knowledge of CHIP's binding specificity, we predicted hundreds of putative interactions arising from caspase activity. Subsequent validation experiments confirmed that CHIP binds the latent C termini at tau and caspase-6. CHIP binding to tau, but not tau, promoted its ubiquitination, while binding to caspase-6 mediated ubiquitin-independent inhibition. Given that caspase activity generates tau in Alzheimer's disease (AD), these results suggested a concise model for CHIP regulation of tau homeostasis. Indeed, we find that loss of CHIP expression in AD coincides with the accumulation of tau and caspase-6. These results illustrate an unanticipated link between caspases and protein homeostasis.
E3 泛素连接酶和蛋白质末端之间的蛋白质-蛋白质相互作用有助于塑造蛋白质组。这些相互作用对蛋白水解很敏感，蛋白水解会改变细胞 N 和 C 末端的整体组成。在这里，我们描述了一种机制，其中半胱天冬酶活性揭示了潜在的 C 末端，然后这些 C 末端被 E3 泛素连接酶 CHIP 识别。利用对 CHIP 结合特异性的扩展知识，我们预测了数百个可能由半胱天冬酶活性产生的潜在相互作用。随后的验证实验证实，CHIP 结合到tau 和 caspase-6 的潜在 C 末端。CHIP 与 tau 的结合而不是 tau 促进了其泛素化，而与 caspase-6 的结合介导了泛素非依赖性抑制。鉴于半胱天冬酶活性在阿尔茨海默病（AD）中产生 tau，这些结果提出了一个简洁的模型，用于 CHIP 调节 tau 动态平衡。事实上，我们发现 AD 中 CHIP 表达的缺失与 tau 和 caspase-6 的积累相一致。这些结果说明了半胱天冬酶和蛋白质动态平衡之间的一个意外联系。
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