Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis
Production of BBF2H7‐derived small peptide fragments via endoplasmic reticulum stress‐dependent regulated intramembrane proteolysis
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通过内质网应激依赖性调节膜内蛋白水解生产 BBF2H7 衍生的小肽片段
DOI：
10.1096/fj.201901748r
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Imaizumi Kazunori
中科院分区：
文献类型：
--
作者：
Matsuhisa Koji;Saito Atsushi;Cai Longjie;Kaneko Masayuki;Okamoto Takumi;Sakaue Fumika;Asada Rie;Urano Fumihiko;Yanagida Kanta;Okochi Masayasu;Kudo Yukitsuka;Matsumoto Masaki;Nakayama Keiichi I.;Imaizumi Kazunori
跨膜蛋白的膜内切割是产生引起生物反应的重要信号的基本细胞过程。这些蛋白水解事件被称为调节性膜内蛋白水解（RIP）。ATF6和BBF2H7是跨膜碱性亮氨酸拉链转录因子，并且响应于内质网（ER）应激而依次受到位点1蛋白酶（S1P）和位点2蛋白酶（S2P）的RIP。然而，负责RIP的转录因子的详细机制，包括精确的切割位点，仍然是未知的。在这项研究中，我们证明了S1P在RXXL S1P识别基序之前切割BBF2H7。相反，S2P切割膜中的至少三个不同位点（紧挨着Leu380、Met381和Leu385），表明S2P在可变位点或通过多步过程切割底物。有趣的是，我们发现BBF2H7衍生的小肽（BSP）片段位于暴露于ER应激的细胞中的S1P和S2P切割位点之间。BSP片段主要由45个氨基酸组成，包括部分跨膜区和管腔区，且易于聚集，类似于β淀粉样蛋白（Aβ）。这些结果推进了对表征不佳的ER应力依赖性RIP的理解。此外，ER应激产生的可聚集肽可能与神经退行性疾病的病理生理学有关。
Intramembrane cleavage of transmembrane proteins is a fundamental cellular process to produce important signals that elicit biological responses. These proteolytic events are known as regulated intramembrane proteolysis (RIP). ATF6 and BBF2H7 are transmembrane basic leucine zipper transcription factors and are subjected to RIP by site‐1 protease (S1P) and site‐2 protease (S2P) sequentially in response to endoplasmic reticulum (ER) stress. However, the detailed mechanisms responsible for RIP of the transcription factors, including the precise cutting sites, are still unknown. In this study, we demonstrated that S1P cleaves BBF2H7 just before the RXXL S1P recognition motif. Conversely, S2P cut at least three different sites in the membrane (next to Leu380, Met381, and Leu385), indicating that S2P cleaves the substrates at variable sites or via a multistep process. Interestingly, we found BBF2H7‐derived small peptide (BSP) fragments located between the S1P and S2P cleavage sites in cells exposed to ER stress. Major type of BSP fragments was composed of 45 amino acid including partial transmembrane and luminal regions and easily aggregates like amyloid β (Aβ) protein. These results advance the understanding of poorly characterized ER stress‐dependent RIP. Furthermore, the aggregable peptides produced by ER stress could link to the pathophysiology of neurodegenerative disorders.
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影响因子：
4.7
作者：
Murakami, T;Kondo, S;Imaizumi, K
通讯作者：
Imaizumi, K
影响因子：
16
作者：
Ye, J;Rawson, RB;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
7.3
作者：
Wolfe, MS;Citron, M;Selkoe, DJ
通讯作者：
Selkoe, DJ
影响因子：
16.6
作者：
Close W;Neumann M;Schmidt A;Hora M;Annamalai K;Schmidt M;Reif B;Schmidt V;Grigorieff N;Fändrich M
通讯作者：
Fändrich M
ER 应激传感器 BBF2H7 的腔域调节软骨细胞增殖。
DOI：
--
发表时间：
2014
期刊：
影响因子：
--
作者：
齋藤敦;今泉和則
通讯作者：
今泉和則