Tolerance to nascent protein misfolding stress requires fine-tuning of the cAMP/PKA pathway.
Tolerance to nascent protein misfolding stress requires fine-tuning of the cAMP/PKA pathway.
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DOI：
10.1016/j.jbc.2021.100690
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Grant CM
中科院分区：
文献类型：
--
作者：
Kritsiligkou P;Nowicki-Osuch K;Carter Z;Kershaw CJ;Creamer DR;Weids AJ;Grant CM
蛋白质聚集是错误折叠的蛋白质异常结合成较大的、通常不溶性的结构，其在衰老期间和蛋白质聚集相关疾病中可能是有毒的。先前的研究已经确定了胞质Tsa 1 peroxiredoxin在响应蛋白质错误折叠应激中的作用。Tsa 1还已知下调cAMP/蛋白激酶A（PKA）通路，作为对过氧化氢应激反应的一部分。然而，cAMP/PKA通路是否参与蛋白质错误折叠应激尚不清楚。使用转录组学，我们研究了对蛋白质错误折叠应激的反应，发现许多应激基因功能的上调和许多与蛋白质合成和其他生长相关过程相关的基因的下调与良好表征的环境应激反应一致。转录反应的范围在野生型和tsa 1突变株中很大程度上相似，但在缺乏Tsa 1的菌株中，其幅度受到抑制。我们确定了正常生长条件下存在的Tsa 1和PKA的Bcy 1调节亚基之间的直接蛋白质相互作用，并解释了观察到的基因表达谱差异。这种相互作用是增加在一个氧化还原依赖性的方式在新生的蛋白质错误折叠，通过Tsa 1介导的氧化Bcy 1。Bcy 1的氧化导致Bcy 1与cAMP结合减少，从而抑制PKA通路活性，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机制，以减轻蛋白质错误折叠应力的毒性后果，这是不同的外源性来源的活性氧引起的压力。
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.
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影响因子：
11.3
作者：
Conrad M;Schothorst J;Kankipati HN;Van Zeebroeck G;Rubio-Texeira M;Thevelein JM
通讯作者：
Thevelein JM
影响因子：
3.2
作者：
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通讯作者：
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作者：
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Nystrom, Thomas
影响因子：
3.3
作者：
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通讯作者：
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影响因子：
64.5
作者：
CAMERON, S;LEVIN, L;WIGLER, M
通讯作者：
WIGLER, M