Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification.
Autophagosome-lysosome fusion is independent of V-ATPase-mediated acidification.
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自噬体 - 散糖体融合与V-ATPase介导的酸化无关。
DOI：
10.1038/ncomms8007
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发表时间：
2015-05-11
影响因子：
16.6
通讯作者：
Neufeld, Thomas P.
中科院分区：
文献类型：
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作者：
Mauvezin, Caroline;Nagy, Peter;Juhasz, Gabor;Neufeld, Thomas P.
依赖于ATP的质子泵V-ATPase确保溶酶体内的低pH，这是溶酶体水解酶活性所必需的。根据对V-ATPase抑制剂BafilmycinA1的研究，溶酶体的酸化也被认为是与来自自噬和内吞途径的进入囊泡融合所必需的。在这里，我们展示了果蝇脂肪体中V-ATPase亚单位的丢失会导致非功能性溶酶体的积累，导致自噬通量的阻断。然而，V-ATPase缺陷的溶酶体仍然能够与自噬小体和内噬小体融合，导致巨型自溶酶体的形成依赖于时间。相反，BafilmycinA1阻止这些细胞中的自噬小体-溶酶体融合，这一缺陷通过耗尽这种药物的次要靶点-钙泵SERCA而表现出来。此外，SERCA的激活以BafilmycinA1敏感的方式促进融合。总而言之，我们的结果表明，溶酶体酸化不是融合的先决条件，BafilmycinA1抑制融合不依赖于它对溶酶体pH的影响。BafilmycinA1是一种自噬抑制剂，可能是由于它对溶酶体质子泵V-ATPase的阻断作用。在这里，作者发现V-ATPase缺陷的溶酶体仍然可以与自噬小体融合，这表明溶酶体酸化和融合是两个可分离的、独立的事件。
The ATP-dependent proton pump V-ATPase ensures low intralysosomal pH, which is essential for lysosomal hydrolase activity. Based on studies with the V-ATPase inhibitor BafilomycinA1, lysosomal acidification is also thought to be required for fusion with incoming vesicles from the autophagic and endocytic pathways. Here we show that loss of V-ATPase subunits in the Drosophila fat body causes an accumulation of non-functional lysosomes, leading to a block in autophagic flux. However, V-ATPase-deficient lysosomes remain competent to fuse with autophagosomes and endosomes, resulting in a time-dependent formation of giant autolysosomes. In contrast, BafilomycinA1 prevents autophagosome–lysosome fusion in these cells, and this defect is phenocopied by depletion of the Ca2+ pump SERCA, a secondary target of this drug. Moreover, activation of SERCA promotes fusion in a BafilomycinA1-sensitive manner. Collectively, our results indicate that lysosomal acidification is not a prerequisite for fusion, and that BafilomycinA1 inhibits fusion independent of its effect on lysosomal pH. BafilomycinA1 is an autophagy inhibitor, presumably owing to its blocking effect on the lysosomal proton pump V-ATPase. Here the authors show that V-ATPase-deficient lysosomes can still fuse with autophagosomes, showing that lysosomal acidification and fusion are two separable, independent events.
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影响因子：
16
作者：
Ganley IG;Wong PM;Gammoh N;Jiang X
通讯作者：
Jiang X
影响因子：
4
作者：
Kilpatrick BS;Eden ER;Schapira AH;Futter CE;Patel S
通讯作者：
Patel S
影响因子：
13.3
作者：
Engedal, Nikolai;Torgersen, Maria L.;Mills, Ian G.
通讯作者：
Mills, Ian G.
影响因子：
16.6
作者：
Kim, Jung;Neufeld, Thomas P.
通讯作者：
Neufeld, Thomas P.
DOI：
10.1007/978-94-007-0763-4_3
发表时间：
2011-01-01
期刊：
CELL FUSION IN HEALTH AND DISEASE: I: CELL FUSION IN HEALTH
影响因子：
--
作者：
Jena, Bhanu P.
通讯作者：
Jena, Bhanu P.