Secretory carrier membrane protein 5 is an autophagy inhibitor that promotes the secretion of α-synuclein via exosome.
Secretory carrier membrane protein 5 is an autophagy inhibitor that promotes the secretion of α-synuclein via exosome.
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分泌载体膜蛋白5是一种自噬抑制剂，通过外泌体促进α-突触核蛋白的分泌
DOI：
10.1371/journal.pone.0180892
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Yang Y;Qin M;Bao P;Xu W;Xu J
自噬-溶酶体途径是一种清除聚集蛋白和受损细胞器的细胞保护系统。同时，外泌体分泌已成为选择性清除神经毒性蛋白（如α-突触核蛋白）的一种模式。越来越多的证据表明，这两个细胞过程是相互协调的，以促进有毒细胞废物的清除;然而，这两个过程之间过渡的调节因子尚不清楚。在这里，我们表明，SCAMP 5，分泌载体膜蛋白显着诱导在亨廷顿氏病患者的大脑中，是快速和短暂的蛋白质应激和自噬刺激诱导，并由主自噬转录调节因子TFEB。具有讽刺意味的是，SCAMP 5通过阻断自噬体和溶酶体的融合来抑制自噬通量。虽然自噬被阻断，但SCAMP 5不会引起细胞中显著的蛋白质聚集。相反，它促进高尔基体片段化并刺激作为外泌体组分的共定位α-突触核蛋白通过外泌体的非常规分泌。因此，我们已经将SCAMP 5鉴定为自噬和外泌体分泌的新型协调者，其在蛋白质应激时被诱导以通过外泌体而不是自噬-溶酶体途径来引导毒性蛋白的有效清除。
Autophagy-lysosomal pathway is a cellular protective system to remove aggregated proteins and damaged organelles. Meanwhile, exosome secretion has emerged as a mode to selectively clear the neurotoxic proteins, such as α-synuclein. Mounting evidence suggests that these two cellular processes are coordinated to facilitate the clearance of toxic cellular waste; however the regulators for the transition between these two processes are unclear. Here we show that SCAMP5, a secretory carrier membrane protein significantly induced in the brains of Huntington's disease patients, is quickly and transiently induced by protein stress and autophagic stimulation, and is regulated by the master autophagy transcriptional regulator TFEB. Ironically, SCAMP5 inhibits autophagy flux by blocking the fusion of autophagosomes and lysosomes. Although autophagy is blocked, SCAMP5 does not cause significant protein aggregation in cells. Instead, it promotes the Golgi fragmentation and stimulates the unconventional secretion of the co-localizing α-synuclein via exosome as an exosome component. Therefore, we have identified SCAMP5 as a novel coordinator of autophagy and exosome secretion, which is induced upon protein stress to channel the efficient clearance of toxic proteins via the exosomes rather than autophagy-lysosomal pathway.
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影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
5.3
作者：
DUBRIDGE, RB;TANG, P;CALOS, MP
通讯作者：
CALOS, MP
影响因子：
16.2
作者：
de Calignon A;Polydoro M;Suárez-Calvet M;William C;Adamowicz DH;Kopeikina KJ;Pitstick R;Sahara N;Ashe KH;Carlson GA;Spires-Jones TL;Hyman BT
通讯作者：
Hyman BT
影响因子：
4.8
作者：
Noh, Jee-Yeon;Lee, Huikyong;Jung, Yong-Keun
通讯作者：
Jung, Yong-Keun
影响因子：
11.4
作者：
Dupont, Nicolas;Jiang, Shanya;Deretic, Vojo
通讯作者：
Deretic, Vojo