Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection.
Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection.
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操纵未折叠蛋白反应：一种对抗冠状病毒感染的药理学策略。
DOI：
10.1371/journal.ppat.1009644
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发表时间：
2021-06
期刊：
影响因子：
6.7
通讯作者：
Irigoyen N
中科院分区：
文献类型：
--
作者：
Echavarría-Consuegra L;Cook GM;Busnadiego I;Lefèvre C;Keep S;Brown K;Doyle N;Dowgier G;Franaszek K;Moore NA;Siddell SG;Bickerton E;Hale BG;Firth AE;Brierley I;Irigoyen N
冠状病毒感染诱导未折叠蛋白反应（UPR），这是一种由三个分支组成的细胞信号传导途径，由内质网（ER）中的未折叠蛋白因高ER负荷而触发。我们已经使用RNA测序和核糖体分析来全面研究小鼠肝炎病毒（MHV）对细胞感染的转录和翻译反应，MHV通常用作最近出现的SARS-CoV-2也属于的β冠状病毒属的模型。我们发现UPR是MHV感染后最显著上调的通路之一。为了证实和扩展这些观察结果，我们通过实验证明了在MHV和SARS-CoV-2感染的细胞中诱导UPR的所有三个分支。SARS-CoV-2 ORF 8或S蛋白的过表达本身就足以诱导UPR。值得注意的是，药物抑制UPR大大降低了MHV和SARS-CoV-2的复制，揭示了该途径对冠状病毒成功复制的重要性。当UPR的IRE 1 α和ATF 6分支都被抑制时，这一点尤其引人注目，减少了SARS-CoV-2病毒体的释放（约1,000倍）。总之，这些数据突出了UPR作为对抗冠状病毒感染的有希望的抗病毒靶点。SARS-CoV-2是导致COVID-19大流行的新型冠状病毒，自2019年底以来已导致超过1. 5亿例病例。大多数感染该病毒的人会出现轻度至中度的呼吸道疾病，无需任何特殊治疗即可康复。然而，老年人和那些有慢性呼吸道疾病等潜在医疗问题的人更有可能患上严重的疾病。到目前为止，已有超过300万人死于COVID-19。不幸的是，没有针对这种病毒性疾病的特定药物。为了产生病毒蛋白并复制其遗传信息，所有冠状病毒都使用称为内质网或ER的细胞结构。然而，病毒蛋白的大量产生和修饰会对ER产生压力，这会激活试图降低ER蛋白水平的补偿性细胞反应。这被称为未折叠蛋白反应或UPR。我们认为，冠状病毒利用UPR的激活来增强其复制。UPR在某些类型的癌症和神经退行性疾病中也被激活，并且已经开发了UPR抑制剂药物来解决这些疾病。在这里，我们还表明，这些化合物可以显着减少SARS-CoV-2在人肺细胞中的复制。
Coronavirus infection induces the unfolded protein response (UPR), a cellular signalling pathway composed of three branches, triggered by unfolded proteins in the endoplasmic reticulum (ER) due to high ER load. We have used RNA sequencing and ribosome profiling to investigate holistically the transcriptional and translational response to cellular infection by murine hepatitis virus (MHV), often used as a model for the Betacoronavirus genus to which the recently emerged SARS-CoV-2 also belongs. We found the UPR to be amongst the most significantly up-regulated pathways in response to MHV infection. To confirm and extend these observations, we show experimentally the induction of all three branches of the UPR in both MHV- and SARS-CoV-2-infected cells. Over-expression of the SARS-CoV-2 ORF8 or S proteins alone is itself sufficient to induce the UPR. Remarkably, pharmacological inhibition of the UPR greatly reduced the replication of both MHV and SARS-CoV-2, revealing the importance of this pathway for successful coronavirus replication. This was particularly striking when both IRE1α and ATF6 branches of the UPR were inhibited, reducing SARS-CoV-2 virion release (~1,000-fold). Together, these data highlight the UPR as a promising antiviral target to combat coronavirus infection. SARS-CoV-2 is the novel coronavirus responsible for the COVID-19 pandemic which has resulted in over 150 million cases since the end of 2019. Most people infected with the virus will experience mild to moderate respiratory illness and recover without any special treatment. However, older people, and those with underlying medical problems like chronic respiratory disease are more likely to develop a serious illness. So far, more than 3 million people have died of COVID-19. Unfortunately, there is no specific medication for this viral disease. In order to produce viral proteins and to replicate their genetic information, all coronaviruses use a cellular structure known as the endoplasmic reticulum or ER. However, the massive production and modification of viral proteins stresses the ER and this activates a compensatory cellular response that tries to reduce ER protein levels. This is termed the unfolded protein response or UPR. We believe that coronaviruses take advantage of the activation of the UPR to enhance their replication. The UPR is also activated in some types of cancer and neurodegenerative disorders and UPR inhibitor drugs have been developed to tackle these diseases. Here, we show also that these compounds can significantly reduce SARS-CoV-2 replication in human lung cells.
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DOI：
10.1126/science.abd3072
发表时间：
2020-11-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Daly JL;Simonetti B;Klein K;Chen KE;Williamson MK;Antón-Plágaro C;Shoemark DK;Simón-Gracia L;Bauer M;Hollandi R;Greber UF;Horvath P;Sessions RB;Helenius A;Hiscox JA;Teesalu T;Matthews DA;Davidson AD;Collins BM;Cullen PJ;Yamauchi Y
通讯作者：
Yamauchi Y
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
5.3
作者：
Baumeister, P;Luo, SZ;Lee, AS
通讯作者：
Lee, AS
影响因子：
7.7
作者：
Andreev DE;O'Connor PB;Fahey C;Kenny EM;Terenin IM;Dmitriev SE;Cormican P;Morris DW;Shatsky IN;Baranov PV
通讯作者：
Baranov PV
影响因子：
13.2
作者：
Chan, Jasper Fuk-Woo;Kok, Kin-Hang;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung