一种可溶性磺基半乳糖基神经酰胺模拟物可促进Delta F508囊性纤维化跨膜传导调节因子从内质网相关降解中逃逸。
A soluble sulfogalactosyl ceramide mimic promotes Delta F508 CFTR escape from endoplasmic reticulum associated degradation.
作者信息
Park Hyun-Joo, Mylvaganum Murugesapillai, McPherson Anne, Fewell Sheara W, Brodsky Jeffrey L, Lingwood Clifford A
机构信息
Research Institute, Division of Molecular Structure and Function, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
出版信息
Chem Biol. 2009 Apr 24;16(4):461-70. doi: 10.1016/j.chembiol.2009.02.014.
AdaSGC binds Hsc70s to inhibit ATPase activity. Using single-turnover assays, adaSGC, a soluble SGC mimic, preferentially inhibited Hsp40-activated Hsc70 ATP hydrolysis (Ki approximately 10 microM) to reduce C-terminal Hsc70-peptide binding and, potentially, chaperone function. ERAD of misfolded Delta F508 CFTR requires Hsc70-Hsp40 chaperones. In transfected baby hamster kidney (BHK) cells, adaSGC increased Delta F508CFTR ERAD escape, and after low-temperature glycerol rescue, maturation, and iodide efflux. Inhibition of SGC biosynthesis reduced Delta F508CFTR but not wtCFTR expression, whereas depletion of other glycosphingolipids had no affect. WtCFTR transfected BHK cells showed increased SGC synthesis compared with Delta F508CFTR/mock-transfected cells. Partial rescue of Delta F508CFTR by low-temperature glycerol increased SGC synthesis. AdaSGC also increased cellular endogenous SGC levels. SGC in the lung, liver, and kidney was severely depleted in Delta F508CFTR compared with wtCFTR mice, suggesting a role for CFTR in SGC biosynthesis.
AdaSGC与Hsc70结合以抑制ATP酶活性。使用单轮测定法，一种可溶性SGC模拟物adaSGC优先抑制Hsp40激活的Hsc70 ATP水解（Ki约为10微摩尔），以减少C末端Hsc70-肽结合，并可能降低伴侣功能。错误折叠的ΔF508 CFTR的内质网相关蛋白降解（ERAD）需要Hsc70-Hsp40伴侣蛋白。在转染的幼仓鼠肾（BHK）细胞中，adaSGC增加了ΔF508CFTR的ERAD逃逸，并在低温甘油挽救、成熟和碘外流后增加。抑制SGC生物合成降低了ΔF508CFTR的表达，但不影响野生型CFTR的表达，而其他糖鞘脂的消耗则没有影响。与ΔF508CFTR/空载体转染细胞相比，野生型CFTR转染的BHK细胞显示SGC合成增加。低温甘油对ΔF508CFTR的部分挽救增加了SGC合成。AdaSGC还增加了细胞内源性SGC水平。与野生型CFTR小鼠相比，ΔF508CFTR小鼠的肺、肝和肾中的SGC严重减少，表明CFTR在SGC生物合成中起作用。
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