Mapping cellular response to destabilized transthyretin reveals cell- and amyloidogenic protein-specific signatures.

IF 5.2 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Amyloid-Journal of Protein Folding Disorders Pub Date : 2023-12-01 Epub Date: 2023-07-13 DOI:10.1080/13506129.2023.2224494

Sabrina Ghosh, Carlos Villacorta-Martin, Jonathan Lindstrom-Vautrin, Devin Kenney, Carly S Golden, Camille V Edwards, Vaishali Sanchorawala, Lawreen H Connors, Richard M Giadone, George J Murphy

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引用次数: 0

Abstract

Background: In ATTR amyloidosis, transthyretin (TTR) protein is secreted from the liver and deposited as toxic aggregates at downstream target tissues. Despite recent advancements in treatments for ATTR amyloidosis, the mechanisms underlying misfolded TTR-mediated cellular damage remain elusive.

Methods: In an effort to define early events of TTR-associated stress, we exposed neuronal (SH-SY5Y) and cardiac (AC16) cells to wild-type and destabilized TTR variants (TTR^V122I (p.V142I) and TTR^L55P (p.L70P)) and performed transcriptional (RNAseq) and epigenetic (ATACseq) profiling. We subsequently compared TTR-responsive signatures to cells exposed to destabilized antibody light chain protein associated with AL amyloidosis as well as ER stressors (thapsigargin, heat shock).

Results: In doing so, we observed overlapping, yet distinct cell type- and amyloidogenic protein-specific signatures, suggesting unique responses to each amyloidogenic variant. Moreover, we identified chromatin level changes in AC16 cells exposed to mutant TTR that resolved upon pre-incubation with kinetic stabilizer tafamidis.

Conclusions: Collectively, these data provide insight into the mechanisms underlying destabilized protein-mediated cellular damage and provide a robust resource representing cellular responses to aggregation-prone proteins and ER stress.

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绘制细胞对不稳定甲状腺素的反应揭示了细胞和淀粉样蛋白特异性特征。

背景:在ATTR淀粉样变性中，转甲状腺素(TTR)蛋白从肝脏分泌，并以毒性聚集体的形式沉积在下游靶组织。尽管最近在ATTR淀粉样变的治疗方面取得了进展，但错误折叠的ttr介导的细胞损伤的机制仍然难以捉摸。方法:为了确定TTR相关应激的早期事件，我们将神经元(SH-SY5Y)和心脏(AC16)细胞暴露于野生型和不稳定的TTR变体(TTRV122I (p.V142I)和TTRL55P (p.L70P))中，并进行转录(RNAseq)和表观遗传(ATACseq)分析。随后，我们比较了暴露于与AL淀粉样变性相关的不稳定抗体轻链蛋白以及内质网应激源(thapsigargin，热休克)的细胞的trr反应特征。结果:在这样做的过程中，我们观察到重叠的，但不同的细胞类型和淀粉样蛋白特异性特征，表明对每个淀粉样变的独特反应。此外，我们发现暴露于突变TTR的AC16细胞的染色质水平变化在动力学稳定剂tafamidis的预孵育后消失。结论:总的来说，这些数据提供了不稳定蛋白介导的细胞损伤机制的见解，并提供了一个强大的资源，代表细胞对聚集易感性蛋白和内质网应激的反应。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Amyloid-Journal of Protein Folding Disorders 生物-生化与分子生物学

CiteScore

10.60

自引率

10.90%

发文量

审稿时长

6-12 weeks

期刊介绍： Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are: etiology, pathogenesis, histopathology, chemical structure, nature of fibrillogenesis; whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders. Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.