The ORF8 protein of SARS-CoV-2 induced endoplasmic reticulum stress and mediated immune evasion by antagonizing production of interferon beta.
The ORF8 protein of SARS-CoV-2 induced endoplasmic reticulum stress and mediated immune evasion by antagonizing production of interferon beta.
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DOI：
10.1016/j.virusres.2021.198350
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发表时间：
2021-04-15
期刊：
影响因子：
5
通讯作者：
Tang S
中科院分区：
文献类型：
--
作者：
Rashid F;Dzakah EE;Wang H;Tang S
开放阅读框架8(Orf8)是SARS-CoV-2的一个辅助蛋白。它由121个氨基酸组成，有orf8L和orf8S两种基因型。在本研究中，我们过表达了SARS-CoV-2的orf8L和orf8S以及SARS-CoV的orf8b，以探讨它们在调节内质网(ER)应激和抑制β干扰素(干扰素)产生中的作用。我们发现，SARS-CoV-2orf8的两个基因型均可通过激活转录因子6(ATF6)和肌醇需要酶1(IRE1)分支来诱导ER应激，但无显著差异。然而，内质网应激途径的第三个分支，即蛋白激酶样ER激酶(PERK)，不受SARS-CoV-2 orf8L或orf8S过表达的影响。此外，SARS-CoV-2的orf8L和orf8S均能下调干扰素和干扰素刺激基因(ISG)、ISG15和ISG56的表达。此外，我们还发现，在Poly(I：C)诱导orf8L和orf8S过表达后，干扰素调节因子3(IRF3)的核转位减少。结果表明，SARS-CoV-2orf8蛋白可以通过激活ATF6和IRE1途径而不是PERK途径来诱导ER应激，并且可以作为干扰素拮抗剂来抑制干扰素的产生。然而，SARS-CoV-2 orf8L和orf8S的基因型别似乎并不影响这些功能。
The open reading frame 8 (orf8) is an accessory protein of SARS-CoV-2. It has 121 amino acids with two genotypes, orf8L and orf8S. In this study, we overexpressed the orf8L and orf8S of SARS-CoV-2 as well as the orf8b of SARS-CoV to investigate their roles in the regulation of endoplasmic reticulum (ER) stress and the inhibition of interferon beta (IFNß) production. We found that the two genotypes of SARS-CoV-2 orf8 are capable of inducing ER stress without significant difference by triggering the activating transcription factor 6 (ATF6) and inositol-requiring enzymes 1 (IRE1) branches of the ER stress pathway. However, the third branch of ER stress pathway, i.e. the protein kinase-like ER kinase (PERK), was unaffected by the overexpression of SARS-CoV-2 orf8L or orf8S. Moreover, both orf8L and orf8S of SARS-CoV-2 are capable of down regulating the production of IFNß and interferon-stimulated genes (ISG), ISG15 and ISG56 induced by polyinosinic-polycytidylic acid (poly (I:C)). Moreover, we also found decreased nuclear translocation of Interferon regulatory factor 3 (IRF3), after overexpressing orf8L and orf8S induced by poly (I:C). Our data demonstrated that SARS-CoV-2 orf8 protein could induce ER stress by activating the ATF6 and IRE1 pathways, but not the PERK pathway, and functions as an interferon antagonist to inhibit the production of IFNß. However, these functions appeared not to be affected by the genotypes of SARS-CoV-2 orf8L and orf8S.
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