Inhibition of Endoplasmic Reticulum-associated Degradation Rescues Native Folding in Loss of Function Protein Misfolding Diseases
Inhibition of Endoplasmic Reticulum-associated Degradation Rescues Native Folding in Loss of Function Protein Misfolding Diseases
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DOI：
10.1074/jbc.m111.274332
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发表时间：
2011-12-16
影响因子：
4.8
通讯作者：
Segatori, Laura
中科院分区：
文献类型：
--
作者：
Wang, Fan;Song, Wensi;Segatori, Laura
溶酶体贮积症通常由破坏天然折叠和损害分泌蛋白运输的突变引起。我们证明，内质网（ER）相关的降解（ERAD）防止天然折叠的突变溶酶体酶在患者来源的成纤维细胞从两个临床上不同的溶酶体贮积症，即戈谢病和泰-萨克斯病。通过ERAD抑制延长ER保留增强了这些不稳定酶变体的折叠、运输和活性。此外，将ERAD抑制与通过蛋白质抑制调节增强细胞折叠能力相结合导致突变酶的协同拯救。ERAD抑制通过用干扰错误折叠底物的识别（kifunensine）或逆易位（eeyarestatin I）的小分子处理细胞来实现。ERAD抑制的这些不同机制显示增强突变蛋白的ER保留，但与显著不同水平的ER应激、未折叠蛋白应答激活和未折叠蛋白应答诱导的细胞凋亡相关。
Lysosomal storage disorders are often caused by mutations that destabilize native folding and impair trafficking of secretory proteins. We demonstrate that endoplasmic reticulum (ER)-associated degradation (ERAD) prevents native folding of mutated lysosomal enzymes in patient-derived fibroblasts from two clinically distinct lysosomal storage disorders, namely Gaucher and Tay-Sachs disease. Prolonging ER retention via ERAD inhibition enhanced folding, trafficking, and activity of these unstable enzyme variants. Furthermore, combining ERAD inhibition with enhancement of the cellular folding capacity via proteostasis modulation resulted in synergistic rescue of mutated enzymes. ERAD inhibition was achieved by cell treatment with small molecules that interfere with recognition (kifunensine) or retrotranslocation (eeyarestatin I) of misfolded substrates. These different mechanisms of ERAD inhibition were shown to enhance ER retention of mutated proteins but were associated with dramatically different levels of ER stress, unfolded protein response activation, and unfolded protein response-induced apoptosis.