自噬
生物
贝肯1
ULK1
未折叠蛋白反应
HMGB1
炎症
内质网
免疫学
细胞激素风暴
综合应力响应
病毒学
细胞生物学
2019年冠状病毒病(COVID-19)
遗传学
基因
医学
细胞凋亡
信使核糖核酸
翻译(生物学)
病理
传染病(医学专业)
疾病
蛋白激酶A
安普克
磷酸化
作者
Xiaolin Zhang,Zixian Yang,Ting Pan,Xubing Long,Qinqin Sun,Pei‐Hui Wang,Xiaojuan Li,Ersheng Kuang
出处
期刊:Autophagy
[Informa]
日期:2022-03-03
卷期号:18 (11): 2576-2592
被引量:24
标识
DOI:10.1080/15548627.2022.2039992
摘要
SARS-CoV-2 infections have resulted in a very large number of severe cases of COVID-19 and deaths worldwide. However, knowledge of SARS-CoV-2 infection, pathogenesis and therapy remains limited, emphasizing the urgent need for fundamental studies and drug development. Studies have shown that induction of macroautophagy/autophagy and hijacking of the autophagic machinery are essential for the infection and replication of SARS-CoV-2; however, the mechanism of this manipulation and the function of autophagy during SARS-CoV-2 infection remain unclear. In the present study, we identified ORF3a as an inducer of autophagy (in particular reticulophagy) and revealed that ORF3a localizes to the ER and induces RETREG1/FAM134B-related reticulophagy through the HMGB1-BECN1 (beclin 1) pathway. As a consequence, ORF3a induces ER stress and inflammatory responses through reticulophagy and then sensitizes cells to the acquisition of an ER stress-related early apoptotic phenotype and facilitates SARS-CoV-2 infection, suggesting that SARS-CoV-2 ORF3a hijacks reticulophagy and then disrupts ER homeostasis to induce ER stress and inflammatory responses during SARS-CoV-2 infection. These findings reveal the sequential induction of reticulophagy, ER stress and acute inflammatory responses during SARS-CoV-2 infection and imply the therapeutic potential of reticulophagy and ER stress-related drugs for COVID-19.Abbreviations: CQ: chloroquine; DEGs: differentially expressed genes; ER: endoplasmic reticulum; GSEA: gene set enrichment analysis; HMGB1: high mobility group box 1; HMOX1: heme oxygenase 1; MERS-CoV: Middle East respiratory syndrome coronavirus; RETREG1/FAM134B: reticulophagy regulator 1; RTN4: reticulon 4; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TN: tunicamycin.
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