Role for LAMP-2 in endosomal cholesterol transport.
Role for LAMP-2 in endosomal cholesterol transport.
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DOI：
10.1111/j.1582-4934.2009.00973.x
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发表时间：
2011-02
影响因子：
5.3
通讯作者：
Eskelinen EL
中科院分区：
文献类型：
--
作者：
Schneede A;Schmidt CK;Hölttä-Vuori M;Heeren J;Willenborg M;Blanz J;Domanskyy M;Breiden B;Brodesser S;Landgrebe J;Sandhoff K;Ikonen E;Saftig P;Eskelinen EL
内体和溶酶体胆固醇运输的机制仍然知之甚少。我们以前表明，未酯化的胆固醇积累在晚期内体和溶酶体中缺乏溶酶体相关膜蛋白-2（LAMP-2）和LAMP-1（晚期内体和溶酶体的两种丰富的膜蛋白）的成纤维细胞的溶酶体中。在这项研究中，我们表明，在缺乏LAMP-1和LAMP-2（LAMP-/-）的细胞中，与野生型细胞相比，低密度脂蛋白（LDL）受体水平和LDL摄取增加。然而，在内源性胆固醇和LDL胆固醇的酯化中存在缺陷。这些结果表明，LAMP−/−细胞在胆固醇转运到内质网酯化位点方面存在缺陷，可能是由于胆固醇从晚期内体或溶酶体中的输出缺陷。我们还发现胆固醇在LAMP-2缺陷的肝脏中积累，并且LAMP-2的过表达延缓了U18666 A诱导的溶酶体胆固醇积累。这些结果指出LAMP-2在内体/溶酶体胆固醇输出中的关键作用。此外，LAMP−/−细胞中晚期内体/溶酶体胆固醇的积累可通过LAMP-2的三种亚型中的任何一种的过表达而减少，但不通过LAMP-1。LAMP-2管腔结构域，特别是膜近端的一半，是必要的和足够的救援效果。综上所述，我们的结果表明，LAMP-2，特别是其管腔结构域，在内体胆固醇转运中起着关键作用，这与LAMP-2的伴侣介导的自噬功能不同。
The mechanisms of endosomal and lysosomal cholesterol traffic are still poorly understood. We showed previously that unesterified cholesterol accumulates in the late endosomes and lysosomes of fibroblasts deficient in both lysosome associated membrane protein-2 (LAMP-2) and LAMP-1, two abundant membrane proteins of late endosomes and lysosomes. In this study we show that in cells deficient in both LAMP-1 and LAMP-2 (LAMP−/−), low-density lipoprotein (LDL) receptor levels and LDL uptake are increased as compared to wild-type cells. However, there is a defect in esterification of both endogenous and LDL cholesterol. These results suggest that LAMP−/− cells have a defect in cholesterol transport to the site of esterification in the endoplasmic reticulum, likely due to defective export of cholesterol out of late endosomes or lysosomes. We also show that cholesterol accumulates in LAMP-2 deficient liver and that overexpression of LAMP-2 retards the lysosomal cholesterol accumulation induced by U18666A. These results point to a critical role for LAMP-2 in endosomal/lysosomal cholesterol export. Moreover, the late endosomal/lysosomal cholesterol accumulation in LAMP−/− cells was diminished by overexpression of any of the three isoforms of LAMP-2, but not by LAMP-1. The LAMP-2 luminal domain, the membrane-proximal half in particular, was necessary and sufficient for the rescue effect. Taken together, our results suggest that LAMP-2, its luminal domain in particular, plays a critical role in endosomal cholesterol transport and that this is distinct from the chaperone-mediated autophagy function of LAMP-2.
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DOI：
10.1083/jcb.137.5.1161
发表时间：
1997-06-02
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gough NR;Fambrough DM
通讯作者：
Fambrough DM
影响因子：
3.9
作者：
CARLSSON, SR;LYCKSELL, PO;FUKUDA, M
通讯作者：
FUKUDA, M
影响因子：
4.8
作者：
Andrejewski, N;Punnonen, EL;Saftig, P
通讯作者：
Saftig, P
影响因子：
3.8
作者：
Chikh, K;Vey, S;Millat, G
通讯作者：
Millat, G
DOI：
10.1083/jcb.123.1.47
发表时间：
1993-10
期刊：
The Journal of cell biology
影响因子：
--
作者：
Huber LA;de Hoop MJ;Dupree P;Zerial M;Simons K;Dotti C
通讯作者：
Dotti C