Quantitative Interactome Proteomics Reveals a Molecular Basis for ATF6-Dependent Regulation of a Destabilized Amyloidogenic Protein
Quantitative Interactome Proteomics Reveals a Molecular Basis for ATF6-Dependent Regulation of a Destabilized Amyloidogenic Protein
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DOI：
10.1016/j.chembiol.2019.04.001
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发表时间：
2019-07-18
影响因子：
8.6
通讯作者：
Wiseman, R. Luke
中科院分区：
文献类型：
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作者：
Plate, Lars;Rius, Bibiana;Wiseman, R. Luke
激活未折叠蛋白反应（UPR）相关转录因子 ATF6 已成为一种有前途的策略，可减少与系统性淀粉样蛋白疾病有关的不稳定淀粉样蛋白的分泌和随后的毒性聚集。然而，ATF6 激活减少淀粉样蛋白分泌的分子机制仍不清楚。我们采用定量相互作用组学平台来定义 ATF6 激活如何减少与轻链淀粉样变性 (AL) 相关的不稳定的淀粉样变性免疫球蛋白轻链 (LC) 的分泌。使用该平台，我们发现 ATF6 激活增加了这种不稳定的 LC 靶向促折叠 ER 蛋白稳态因子的子集，这些因子将淀粉样蛋白形成的 LC 保留在 ER 内，防止其分泌。我们的结果定义了 ATF6 依赖性减少不稳定 LC 分泌的分子基础，并强调了靶向这种 UPR 相关转录因子以减少与 AL 和相关系统性淀粉样蛋白疾病有关的不稳定淀粉样蛋白分泌的优势。
Activation of the unfolded protein response (UPR)-associated transcription factor ATF6 has emerged as a promising strategy to reduce the secretion and subsequent toxic aggregation of destabilized, amyloidogenic proteins implicated in systemic amyloid diseases. However, the molecular mechanism by which ATF6 activation reduces the secretion of amyloidogenic proteins remains poorly defined. We employ a quantitative interactomics platform to define how ATF6 activation reduces secretion of a destabilized, amyloidogenic immunoglobulin light chain (LC) associated with light-chain amyloidosis (AL). Using this platform, we show that ATF6 activation increases the targeting of this destabilized LC to a subset of pro-folding ER proteostasis factors that retains the amyloidogenic LC within the ER, preventing its secretion. Our results define a molecular basis for the ATF6-dependent reduction in destabilized LC secretion and highlight the advantage for targeting this UPR-associated transcription factor to reduce secretion of destabilized, amyloidogenic proteins implicated in AL and related systemic amyloid diseases.