ANO5 ensures trafficking of annexins in wounded myofibers.
ANO5 ensures trafficking of annexins in wounded myofibers.
复制标题
ANO5确保膜联蛋白在受伤的肌纤维中的运输。
DOI：
10.1083/jcb.202007059
复制
发表时间：
2021-03-01
期刊：
影响因子：
--
通讯作者：
Hartzell HC
中科院分区：
文献类型：
--
作者：
Foltz SJ;Cui YY;Choo HJ;Hartzell HC
ANO5的突变导致肢带型肌营养不良，其特征是膜修复缺陷，使肌肉更容易受到正常使用的永久性损伤。这项工作将ANO5缺陷肌肉中失败的膜修复与膜联蛋白（关键修复蛋白）的运输改变联系起来。ANO5（TMEM16E）突变导致肢带型肌营养不良症R12。有缺陷的质膜修复是一种可能的机制。使用从ANO5敲除小鼠的肌纤维，我们表明，贩运的几个膜联蛋白的蛋白质，一起形成一个帽子在损伤部位，改变后的损失ANO5。膜联蛋白A2在伤口处积累到WT纤维中观察到的水平的近两倍，而膜联蛋白A6积累在不存在ANO5的情况下基本上被抑制。膜联蛋白A1和A5在帽上的出现同样在Ano5敲除中减少。这些变化与膜联蛋白修复帽精细结构的改变和膜联蛋白阳性囊泡的脱落相关。我们的结论是，在修复过程中膜联蛋白协调的损失是破坏Ano5基因敲除小鼠和缺陷修复表型的基础。虽然ANO5是一种磷脂乱序酶，但异常修复可通过乱序酶缺陷型ANO5突变体的过表达来挽救，这表明ANO5在修复中具有一种新的、不依赖于乱序酶的作用。
Mutations in ANO5 cause a limb-girdle muscular dystrophy characterized by membrane repair defects that make muscles more susceptible to permanent damage from normal use. This work links failed membrane repair in ANO5-deficient muscle to altered trafficking of the annexins, crucial repair proteins. Mutations in ANO5 (TMEM16E) cause limb-girdle muscular dystrophy R12. Defective plasma membrane repair is a likely mechanism. Using myofibers from Ano5 knockout mice, we show that trafficking of several annexin proteins, which together form a cap at the site of injury, is altered upon loss of ANO5. Annexin A2 accumulates at the wound to nearly twice the level observed in WT fibers, while annexin A6 accumulation is substantially inhibited in the absence of ANO5. Appearance of annexins A1 and A5 at the cap is likewise diminished in the Ano5 knockout. These changes are correlated with an alteration in annexin repair cap fine structure and shedding of annexin-positive vesicles. We conclude that loss of annexin coordination during repair is disrupted in Ano5 knockout mice and underlies the defective repair phenotype. Although ANO5 is a phospholipid scramblase, abnormal repair is rescued by overexpression of a scramblase-defective ANO5 mutant, suggesting a novel, scramblase-independent role of ANO5 in repair.
登录
查看更多内容
影响因子：
16.6
作者：
Boye TL;Maeda K;Pezeshkian W;Sønder SL;Haeger SC;Gerke V;Simonsen AC;Nylandsted J
通讯作者：
Nylandsted J
影响因子：
6.8
作者：
Brunner, Janine D.;Schenck, Stephan;Dutzler, Raimund
通讯作者：
Dutzler, Raimund
影响因子：
3.3
作者：
Barthelemy, Florian;Defour, Aurelia;Bartoli, Marc
通讯作者：
Bartoli, Marc
影响因子：
16.6
作者：
Bouter A;Gounou C;Bérat R;Tan S;Gallois B;Granier T;d'Estaintot BL;Pöschl E;Brachvogel B;Brisson AR
通讯作者：
Brisson AR
影响因子：
3.9
作者：
Di Zanni, Eleonora;Gradogna, Antonella;Boccaccio, Anna
通讯作者：
Boccaccio, Anna