SARS-CoV-2 ORF3A interacts with the Clic-like chloride channel-1 (CLCC1) and triggers an unfolded protein response.
SARS-CoV-2 ORF3A interacts with the Clic-like chloride channel-1 (CLCC1) and triggers an unfolded protein response.
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作者：
Gruner HN;Zhang Y;Shariati K;Yiv N;Hu Z;Wang Y;Hejtmancik JF;McManus MT;Tharp K;Ku G
了解SARS-CoV-2与宿主细胞机制之间的相互作用可能会揭示治疗COVID-19的新靶点。我们重点研究了SARS-CoV-2 ORF3A辅助蛋白与clic样氯通道-1 （CLCC1）之间的相互作用。我们发现ORF3A与CLCC1部分共定位，ORF3A和CLCC1可以共免疫沉淀。由于CLCC1在未折叠蛋白反应（UPR）中发挥作用，我们假设ORF3A也可能在UPR中发挥作用。事实上，ORF3A的表达触发了与CLCC1敲低相似的转录UPR。ORF3A在293T细胞中的表达诱导细胞死亡，并通过化学伴侣牛磺酸去氧胆酸（TUDCA）来挽救细胞死亡。CLCC1敲低的细胞受到orf3a介导的细胞死亡的部分保护。CLCC1敲低可上调ORF3A表达诱导的几个稳态UPR靶点，包括HSPA6和剪接的XBP1，而这些靶点不会被ORF3A进一步上调。我们的数据表明CLCC1沉默触发稳态UPR的模型可以防止ORF3A表达导致的细胞死亡。
Understanding the interactions between SARS-CoV-2 and host cell machinery may reveal new targets to treat COVID-19. We focused on an interaction between the SARS-CoV-2 ORF3A accessory protein and the CLIC-like chloride channel-1 (CLCC1). We found that ORF3A partially co-localized with CLCC1 and that ORF3A and CLCC1 could be co-immunoprecipitated. Since CLCC1 plays a role in the unfolded protein response (UPR), we hypothesized that ORF3A may also play a role in the UPR. Indeed, ORF3A expression triggered a transcriptional UPR that was similar to knockdown of CLCC1. ORF3A expression in 293T cells induced cell death and this was rescued by the chemical chaperone taurodeoxycholic acid (TUDCA). Cells with CLCC1 knockdown were partially protected from ORF3A-mediated cell death. CLCC1 knockdown upregulated several of the homeostatic UPR targets induced by ORF3A expression, including HSPA6 and spliced XBP1, and these were not further upregulated by ORF3A. Our data suggest a model where CLCC1 silencing triggers a homeostatic UPR that prevents cell death due to ORF3A expression.
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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：
29
作者：
Lerner AG;Upton JP;Praveen PV;Ghosh R;Nakagawa Y;Igbaria A;Shen S;Nguyen V;Backes BJ;Heiman M;Heintz N;Greengard P;Hui S;Tang Q;Trusina A;Oakes SA;Papa FR
通讯作者：
Papa FR
影响因子：
5.6
作者：
Batra N;De Souza C;Batra J;Raetz AG;Yu AM
通讯作者：
Yu AM
细胞内氯离子通道 CLCC1 突变与常染色体隐性遗传色素性视网膜炎相关
影响因子：
4.5
作者：
Li L;Jiao X;D'Atri I;Ono F;Nelson R;Chan CC;Nakaya N;Ma Z;Ma Y;Cai X;Zhang L;Lin S;Hameed A;Chioza BA;Hardy H;Arno G;Hull S;Khan MI;Fasham J;Harlalka GV;Michaelides M;Moore AT;Coban Akdemir ZH;Jhangiani S;Lupski JR;Cremers FPM;Qamar R;Salman A;Chilton J;Self J;Ayyagari R;Kabir F;Naeem MA;Ali M;Akram J;Sieving PA;Riazuddin S;Baple EL;Riazuddin SA;Crosby AH;Hejtmancik JF
通讯作者：
Hejtmancik JF
影响因子：
3.5
作者：
Belal, Cherine;Ameli, Neema J.;Chan, Sic L.
通讯作者：
Chan, Sic L.