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自噬在人类疾病中的作用
Autophagy in Human Diseases


Noboru Mizushima ... 其他 • 2020.10.15
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自噬是细胞结构在溶酶体中降解的过程。自噬(最初在酵母中发现)关键基因的阐明使我们对哺乳动物生理学和人类疾病病理生理学的理解进入了新时代。自噬相关基因的突变与多种人类疾病相关,这为我们发现自噬通路中的新治疗靶点提供了线索。

 

膜动力学和自噬的分子机制


在自噬过程中,细胞质在溶酶体中降解1-3。因为溶酶体有作为安全机制的界膜,可阻止降解酶的渗漏,所以自噬过程涉及复杂的膜动力学。人们观察到三种类型的自噬,它们将被降解的细胞内容物(cargo)运输到溶酶体的方式不同:巨自噬、微自噬和分子伴侣介导的自噬(图1)。巨自噬是对环境和生理信号做出应答时,主要的可调控形式的自噬。微自噬是溶酶体直接吞噬细胞质内容物8,而分子伴侣介导的自噬是分子伴侣协助底物蛋白(可能还有DNA和RNA)完成跨溶酶体膜的转运9,10。我们在本综述中主要关注巨自噬过程。

 

图1. 自噬的类型

巨自噬(图A)是由自噬体介导1-5。细胞质的一部分被称为隔离膜的薄膜储藏结构或吞噬泡包裹,形成自噬体。与溶酶体融合后,包裹的内容物在自噬溶酶体内被溶酶体酶降解。哺乳动物细胞内自噬体的形成是由UNC-51样激酶1或2(ULK1或ULK2)、ATG13、RB1CC1(也称为ATG11或FIP200)和ATG101构成的蛋白激酶复合物启动。这一起始复合物可接收两类信号。第一类包括各种营养素和应激信号,主要集中在mTORC1(雷帕霉素复合体1的机械作用靶点)上;mTORC1可被氨基酸和生长因子(如胰岛素)激活,并抑制ULK1/2。在饥饿状态下,这种抑制功能被启动,导致起始复合物转运到自噬体形成的位点,该位点在内质网(ER)或密切相关的膜上。此外,低能量状态通过AMP活化蛋白激酶(AMPK)激活ULK1/2。第二类信号涉及自噬细胞内容物,如受损的线粒体,这类信号也可通过与RB1CC1直接相互作用的方式激活起始复合物。为了使自噬体膜成核,ULK1/2将Ⅲ类磷脂酰肌醇3-激酶(PI3K)复合物的成分磷酸化,包括ATG14、Beclin 1、VPS34和VPS15,并在自噬体前体膜上产生磷脂酰肌醇3-磷酸(PI3P)。第二类信号还涉及ATG9囊泡。接下来,与PI3P相互作用的WIPI家族蛋白(WIPI)和脂质转移蛋白ATG2A/B被募集。

在内质网上,形成自噬体还需要多次跨膜蛋白VMP1和TMEM41B(很可能是在延长步骤)。WIPI2募集由ATG12-ATG5和ATG16L1构成的复合物,该复合物可促进ATG8家族蛋白(LC3和GABARAP子家族)和磷脂酰乙醇胺(PE)之间的结合。目前认为ATG8家族蛋白对于膜延长和自噬体闭合非常重要。

一旦自噬体边缘通过ESCRT(转运必需内体分选复合物)机制封闭,自噬体将获得SNAP受体(SNARE)蛋白,如突触融合蛋白(syntaxin)17(STX17)和YKT6,它们与SNAP29和溶酶体SNARE蛋白(如VAMP7、VAMP8和STX7)相互作用,促进与溶酶体的融合。融合步骤由拴系(tethering)机制(如HOPS复合物、EPG5和PLEKHM1)调节。内层自噬体膜上的ATG8家族蛋白可选择性识别被降解的细胞内容物,如线粒体(线粒体自噬)、内质网片段(内质网自噬)、溶酶体(溶酶体自噬)、蛋白质聚合物(聚合物自噬)和铁蛋白(铁蛋白自噬)3,6,7。ATG8蛋白可直接识别具有LIR(LC3相互作用区域)的底物蛋白,或通过含有LIR的衔接蛋白间接识别它们,这些衔接蛋白可以是被降解细胞内容物特异性的(如线粒体自噬和内质网自噬衔接蛋白),也可以是被降解细胞内容物非特异性的(可溶性衔接蛋白)。可溶性衔接蛋白常识别泛素化的被降解细胞内容物。

微自噬(图B)是由溶酶体膜直接吞噬一部分细胞质8。在分子伴侣介导的自噬(图C)中,细胞质分子伴侣和溶酶体膜转运体将未折叠的蛋白转运到溶酶体腔内9。细胞质RNA和DNA可通过类似机制被降解(称为RAN自噬-DNA自噬)(图中未显示)10。Ub表示泛素。

 

在巨自噬中,细胞质的一部分被称为隔离膜的薄膜储藏结构或吞噬泡(phagophore)吞入,因而形成称为自噬体的双层膜细胞器(图1)。外层自噬体膜和溶酶体膜融合后,溶酶体酶将内层自噬体膜和自噬体内容物降解。巨自噬过程曾被认为是非选择性的,但我们现在已经了解到巨自噬可选择性地降解细胞内容物,如受损的线粒体(线粒体自噬)、破裂的溶酶体(溶酶体自噬)和细胞内的微生物(异体自噬)(图1)3,6,7。巨自噬可降解各种大分子和整个细胞器,而蛋白酶体是逐一降解泛素化蛋白。这两种主要的降解通路在功能上有联系,甚至有共同的关键分子。例如,泛素不仅是蛋白酶体的信号,也是巨自噬的信号(图1)7





作者信息

Noboru Mizushima, M.D., Ph.D., and Beth Levine, M.D.
From the Department of Biochemistry and Molecular Biology, Graduate School and Faculty of Medicine, University of Tokyo, Tokyo (N.M.); and the Center for Autophagy Research, Department of Internal Medicine and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas (B.L.). Address reprint requests to Dr. Mizushima at the Department of Biochemistry and Molecular Biology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, or at nmizu@m.u-tokyo.ac.jp. Beth Levine, M.D., is deceased.

 

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