Endoplasmic reticulum tubules limit the size of misfolded protein condensates.
Endoplasmic reticulum tubules limit the size of misfolded protein condensates.
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内质网小管限制错误折叠的蛋白质浓缩物的大小。
DOI：
10.7554/elife.71642
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发表时间：
2021-09-01
期刊：
影响因子：
7.7
通讯作者：
Ferro-Novick S
中科院分区：
文献类型：
--
作者：
Parashar S;Chidambaram R;Chen S;Liem CR;Griffis E;Lambert GG;Shaner NC;Wortham M;Hay JC;Ferro-Novick S
内质网（ER）由片层和小管组成。在这里，我们报告说，COPII外壳亚基，SEC 24 C，工程与长形式的管状ER-吞噬受体，RTN 3，目标显性干扰突变体胰岛素原秋田点状溶酶体。当秋田斑点向溶酶体的传递被破坏时，大的斑点在ER中积累。出乎意料的是，光漂白分析表明，秋田斑点表现为缩合物，而不是聚集体，如前所述。当RTN 3或SEC 24 C被耗尽时，或者当ER片层通过敲除Lunapark或过表达CLIMP 63而增殖时，秋田斑点扩大。其他ER-吞噬底物被分离到小管中，表现得像秋田，而被ER-吞噬片受体FAM 134 B降解的底物（I型前胶原）则没有。相反，当ER小管在Lunpark敲除细胞中通过过度表达网织红细胞而增加时，ER-吞噬增加并且大秋田斑点的数量减少。我们的研究结果表明，分离货物进入小管有两个有益的作用。首先，它将突变的错误折叠蛋白、受体和SEC 24 C定位到相同的ER结构域。其次，在它们经历ER-吞噬之前，物理地限制小管内的冷凝物，防止它们扩大和影响细胞健康。
The endoplasmic reticulum (ER) is composed of sheets and tubules. Here we report that the COPII coat subunit, SEC24C, works with the long form of the tubular ER-phagy receptor, RTN3, to target dominant-interfering mutant proinsulin Akita puncta to lysosomes. When the delivery of Akita puncta to lysosomes was disrupted, large puncta accumulated in the ER. Unexpectedly, photobleach analysis indicated that Akita puncta behaved as condensates and not aggregates, as previously suggested. Akita puncta enlarged when either RTN3 or SEC24C were depleted, or when ER sheets were proliferated by either knocking out Lunapark or overexpressing CLIMP63. Other ER-phagy substrates that are segregated into tubules behaved like Akita, while a substrate (type I procollagen) that is degraded by the ER-phagy sheets receptor, FAM134B, did not. Conversely, when ER tubules were augmented in Lunapark knock-out cells by overexpressing reticulons, ER-phagy increased and the number of large Akita puncta was reduced. Our findings imply that segregating cargoes into tubules has two beneficial roles. First, it localizes mutant misfolded proteins, the receptor, and SEC24C to the same ER domain. Second, physically restraining condensates within tubules, before they undergo ER-phagy, prevents them from enlarging and impacting cell health.