Adenovirus RID-alpha activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C.
Adenovirus RID-alpha activates an autonomous cholesterol regulatory mechanism that rescues defects linked to Niemann-Pick disease type C.
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DOI：
10.1083/jcb.200903039
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发表时间：
2009-11-16
期刊：
影响因子：
--
通讯作者：
Carlin CR
中科院分区：
文献类型：
--
作者：
Cianciola NL;Carlin CR
病毒对胆固醇稳态的颠覆提供了对类固醇运输、自噬和溶酶体储存疾病的洞察。寄主-病原体相互作用是理解细胞基本生物学过程的重要模型系统。在这项研究中，我们描述了由腺病毒膜蛋白RID-α诱导的胆固醇运输途径，该途径也在急性感染的早期阶段颠覆了细胞自噬途径。棕榈酰化缺陷的RID-α突变体解除对胆固醇稳态的调节，并引起溶酶体储存异常，类似于与尼曼-皮克C型(NPC)病相关的突变。野生型RID-α通过涉及III类磷脂酰肌醇-3-激酶的机制修复这种疾病患者细胞中的脂质分类缺陷。与定位于晚期内体/溶酶体的鼻咽癌疾病基因产物不同，RID-α诱导具有独特分子组成的自噬样囊泡的积累。异位RID-α在两个不同的水平上调节细胞内胆固醇的运输：从内小体出口和向内质网运输，这是动态平衡基因调节所必需的。然而，RID-α也诱导了一种新的细胞表型，表明它激活了一种不同于鼻咽癌疾病基因产物的自主胆固醇调节机制。
Viral subversion of cholesterol homeostasis provides insights into sterol trafficking, autophagy, and lysosomal storage diseases. Host–pathogen interactions are important model systems for understanding fundamental cell biological processes. In this study, we describe a cholesterol-trafficking pathway induced by the adenovirus membrane protein RID-α that also subverts the cellular autophagy pathway during early stages of an acute infection. A palmitoylation-defective RID-α mutant deregulates cholesterol homeostasis and elicits lysosomal storage abnormalities similar to mutations associated with Niemann-Pick type C (NPC) disease. Wild-type RID-α rescues lipid-sorting defects in cells from patients with this disease by a mechanism involving a class III phosphatidylinositol-3-kinase. In contrast to NPC disease gene products that are localized to late endosomes/lysosomes, RID-α induces the accumulation of autophagy-like vesicles with a unique molecular composition. Ectopic RID-α regulates intracellular cholesterol trafficking at two distinct levels: the egress from endosomes and transport to the endoplasmic reticulum necessary for homeostatic gene regulation. However, RID-α also induces a novel cellular phenotype, suggesting that it activates an autonomous cholesterol regulatory mechanism distinct from NPC disease gene products.
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影响因子：
64.5
作者：
CARLIN, CR;TOLLEFSON, AE;WOLD, WSM
通讯作者：
WOLD, WSM
影响因子：
13.3
作者：
Ichimura, Yoshinobu;Kominami, Eiki;Komatsu, Masaaki
通讯作者：
Komatsu, Masaaki
DOI：
10.1083/jcb.200610151
发表时间：
2007-01-29
期刊：
The Journal of cell biology
影响因子：
--
作者：
Greaves J;Chamberlain LH
通讯作者：
Chamberlain LH
影响因子：
4.5
作者：
Fader, Claudio M.;Sanchez, Diego;Colombo, Maria I.
通讯作者：
Colombo, Maria I.
影响因子：
4
作者：
Gutierrez, MG;Munafó, DB;Colombo, MI
通讯作者：
Colombo, MI