Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
J Biol Chem. 2021 Jan-Jun;296:100690. doi: 10.1016/j.jbc.2021.100690. Epub 2021 Apr 22.
Protein aggregation is the abnormal association of misfolded proteins into larger, often insoluble structures that can be toxic during aging and in protein aggregation-associated diseases. Previous research has established a role for the cytosolic Tsa1 peroxiredoxin in responding to protein misfolding stress. Tsa1 is also known to downregulate the cAMP/protein kinase A (PKA) pathway as part of the response to hydrogen peroxide stress. However, whether the cAMP/PKA pathway is involved in protein misfolding stress is not known. Using transcriptomics, we examined the response to protein misfolding stress and found upregulation of numerous stress gene functions and downregulation of many genes related to protein synthesis and other growth-related processes consistent with the well-characterized environmental stress response. The scope of the transcriptional response is largely similar in wild-type and tsa1 mutant strains, but the magnitude is dampened in the strain lacking Tsa1. We identified a direct protein interaction between Tsa1 and the Bcy1 regulatory subunit of PKA that is present under normal growth conditions and explains the observed differences in gene expression profiles. This interaction is increased in a redox-dependent manner in response to nascent protein misfolding, via Tsa1-mediated oxidation of Bcy1. Oxidation of Bcy1 causes a reduction in cAMP binding by Bcy1, which dampens PKA pathway activity, leading to a targeted reprogramming of gene expression. Redox regulation of the regulatory subunit of PKA provides a mechanism to mitigate the toxic consequences of protein misfolding stress that is distinct to stress caused by exogenous sources of reactive oxygen species.
蛋白质聚集是指错误折叠的蛋白质异常聚集形成较大的、通常不溶的结构，这种结构在衰老和与蛋白质聚集相关的疾病中可能具有毒性。先前的研究已经确定细胞质 Tsa1 过氧化物酶在应对蛋白质错误折叠应激方面的作用。Tsa1 还已知下调 cAMP/蛋白激酶 A (PKA) 途径，作为应对过氧化氢应激的一部分。然而，cAMP/PKA 途径是否参与蛋白质错误折叠应激尚不清楚。我们使用转录组学研究了蛋白质错误折叠应激的反应，发现许多应激基因功能上调，许多与蛋白质合成和其他生长相关过程相关的基因下调，与特征明确的环境应激反应一致。转录反应的范围在野生型和 tsa1 突变株中基本相似，但在缺乏 Tsa1 的菌株中反应幅度减弱。我们鉴定了 Tsa1 和 PKA 的 Bcy1 调节亚基之间的直接蛋白质相互作用，该相互作用在正常生长条件下存在，并解释了观察到的基因表达谱差异。这种相互作用通过 Tsa1 介导的 Bcy1 氧化以依赖氧化还原的方式增加，以应对新形成的蛋白质错误折叠。Bcy1 的氧化导致 Bcy1 结合 cAMP 的减少，从而抑制 PKA 途径活性，导致基因表达的靶向重编程。PKA 调节亚基的氧化还原调节提供了一种减轻蛋白质错误折叠应激毒性后果的机制，这种机制与由外源性活性氧物质引起的应激不同。
