ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors.
ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors.
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DOI：
10.3390/cells11101661
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发表时间：
2022-05-17
期刊：
影响因子：
6
通讯作者：
Wiseman, R. Luke
中科院分区：
文献类型：
--
作者：
Mesgarzadeh, Jaleh S.;Romine, Isabelle C.;Smith-Cohen, Ethan M.;Grandjean, Julia M. D.;Kelly, Jeffery W.;Genereux, Joseph C.;Wiseman, R. Luke
关键词：
不稳定的甲状腺素运载蛋白（TTR）变体的细胞外聚集与家族性TTR相关淀粉样蛋白疾病的发病和发病机制有关。减少TTR的毒性细胞外聚集的一种策略是减少从哺乳动物细胞分泌的易聚集蛋白的群体。未折叠蛋白反应（UPR）相关转录因子ATF6的应激非依赖性激活优先降低不稳定的、易于聚集的TTR变体的分泌和随后的聚集。然而，这种减少分泌的机制以前是不确定的。在这里，我们实现了一个基于质谱的interactomics方法来确定内质网（ER）蛋白质稳态因子参与ATF6依赖性减少不稳定的TTR分泌。我们表明，ATF6激活减少淀粉样蛋白TTR分泌和随后的聚集通过一种机制，涉及ER保留，这是由增加相互作用与ATF6调节ER蛋白抑制因子，包括BiP和PDIA4介导的。有趣的是，TTR的PDIA 4依赖性保留独立于单个TTR半胱氨酸残基和PDIA 4的氧化还原活性，表明PDIA 4通过氧化还原非依赖性机制将不稳定的TTR保留在ER中。我们的研究结果定义了一个机制的基础，以解释ATF6激活依赖性减少不稳定，淀粉样蛋白TTR分泌，可以治疗访问，以改善TTR相关的淀粉样蛋白疾病的治疗。
The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce the toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone proteins secreted from mammalian cells. The stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases the secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass-spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions in destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent mechanism. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction in destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases.
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影响因子：
3.7
作者：
Coelho T;Merlini G;Bulawa CE;Fleming JA;Judge DP;Kelly JW;Maurer MS;Planté-Bordeneuve V;Labaudinière R;Mundayat R;Riley S;Lombardo I;Huertas P
通讯作者：
Huertas P
DOI：
10.1083/jcb.202112104
发表时间：
2022-04-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mesgarzadeh JS;Buxbaum JN;Wiseman RL
通讯作者：
Wiseman RL
影响因子：
8.6
作者：
Plate, Lars;Rius, Bibiana;Wiseman, R. Luke
通讯作者：
Wiseman, R. Luke
影响因子：
15
作者：
Choi, Sungwook;Ong, Derrick Sek Tong;Kelly, Jeffery W.
通讯作者：
Kelly, Jeffery W.
DOI：
10.1007/s00018-009-0109-0
发表时间：
2009-10
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Buxbaum JN;Reixach N
通讯作者：
Reixach N