tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2022 Oct 11;119(41):e2209042119.
doi: 10.1073/pnas.2209042119. Epub 2022 Sep 22.
Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins
Fengwen Zhang[SUP] 1 [/SUP], Trinity M Zang[SUP] 1 [/SUP], Eva M Stevenson[SUP] 2 [/SUP], Xiao Lei[SUP] 1 [/SUP], Dennis C Copertino[SUP] 2 [/SUP], Talia M Mota[SUP] 2 [/SUP], Julie Boucau[SUP] 3 [/SUP], Wilfredo F Garcia-Beltran[SUP] 3 4 [/SUP], R Brad Jones[SUP] 2 [/SUP], Paul D Bieniasz[SUP] 1 5 [/SUP]
Affiliations
Abstract
Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8[SUP]+[/SUP] cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately fivefold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I down-regulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I down-regulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8[SUP]+[/SUP] T cells. Specifically, ORF7a prevented the assembly of the MHC-I peptide loading complex and caused retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.
Keywords: MHC-I down-regulation; ORF7a; Peptide loading complex; SARS-CoV-2; Sarbecovirus.
. 2022 Oct 11;119(41):e2209042119.
doi: 10.1073/pnas.2209042119. Epub 2022 Sep 22.
Inhibition of major histocompatibility complex-I antigen presentation by sarbecovirus ORF7a proteins
Fengwen Zhang[SUP] 1 [/SUP], Trinity M Zang[SUP] 1 [/SUP], Eva M Stevenson[SUP] 2 [/SUP], Xiao Lei[SUP] 1 [/SUP], Dennis C Copertino[SUP] 2 [/SUP], Talia M Mota[SUP] 2 [/SUP], Julie Boucau[SUP] 3 [/SUP], Wilfredo F Garcia-Beltran[SUP] 3 4 [/SUP], R Brad Jones[SUP] 2 [/SUP], Paul D Bieniasz[SUP] 1 5 [/SUP]
Affiliations
- PMID: 36136978
- DOI: 10.1073/pnas.2209042119
Abstract
Viruses employ a variety of strategies to escape or counteract immune responses, including depletion of cell surface major histocompatibility complex class I (MHC-I), that would ordinarily present viral peptides to CD8[SUP]+[/SUP] cytotoxic T cells. As part of a screen to elucidate biological activities associated with individual severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) viral proteins, we found that ORF7a reduced cell surface MHC-I levels by approximately fivefold. Nevertheless, in cells infected with SARS-CoV-2, surface MHC-I levels were reduced even in the absence of ORF7a, suggesting additional mechanisms of MHC-I down-regulation. ORF7a proteins from a sample of sarbecoviruses varied in their ability to induce MHC-I down-regulation and, unlike SARS-CoV-2, the ORF7a protein from SARS-CoV lacked MHC-I downregulating activity. A single amino acid at position 59 (T/F) that is variable among sarbecovirus ORF7a proteins governed the difference in MHC-I downregulating activity. SARS-CoV-2 ORF7a physically associated with the MHC-I heavy chain and inhibited the presentation of expressed antigen to CD8[SUP]+[/SUP] T cells. Specifically, ORF7a prevented the assembly of the MHC-I peptide loading complex and caused retention of MHC-I in the endoplasmic reticulum. The differential ability of ORF7a proteins to function in this way might affect sarbecovirus dissemination and persistence in human populations, particularly those with infection- or vaccine-elicited immunity.
Keywords: MHC-I down-regulation; ORF7a; Peptide loading complex; SARS-CoV-2; Sarbecovirus.