摘要
高温度要求 A1 (HtrA1 ) 属于被连接到各种各样的人的混乱的一个古老的蛋白质家庭。exon 1-encoded N 终端领域的精确角色并且这些怎么影响人的 HtrA1 的生物功能留下逃犯。在这研究，我们在脊椎动物的最近的普通祖先跟踪了这些 N 终端领域的进化起源到一个单个基因熔化事件。我们假设了那人的 HtrA1 在展开的蛋白质反应被含有。在网膜的 pigmented epithelia 的高度能分泌的房间， endoplasmic 蜂窝胃(嗯) 压力 upregulated HtrA1。与以高度形成树枝状的时尚的 vimentin 中介细丝 co 局部性的 HtrA1。在之上嗯应力，沿着中间的细丝追踪的 HtrA1，它崩溃了并且在微导管绑在 aggresome 组织中心。HtrA1 的基因 silencing 改变了适应发信号的时间表和振幅并且附随地导致了 apoptosis。野类型的 HtrA1 的恢复，然而并非它的朊酶不活跃的异种，必要、足够保护免受 apoptosis 的伤害。怀有 1 替换显示了的 exon 的 HtrA1 的变体从 proteotoxicity 在 rescuing 房间减少了功效。我们的结果在 proteostasis 在 HtrA1 对蛋白质错误褶层和缺点的含意在哺乳动物的房间的工具箱照亮 HtrA1 的集成。
High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrAZ remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is impticated in unfotded protein response. ｜n highly secre- tory cells of the retinal pigmented epithelia, endoplasmic reticulum （ER） stress upregulated HtrA1. HtrA1 co-localized with vimen- tin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions dis- played reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mam- malian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.
