Mary Wilson
Well-known member
December 27, 2022
https://doi.org/10.1073/pnas.2208525120
Najla Arshad, Maudry Laurent-Rolle, Wesam S. Ahmed, Jack Chun-Chieh Hsu, Susan M. Mitchell, Joanna Pawlak, Debrup Sengupta, Kabir H. Biswas, and Peter Cresswell
Significance
Viruses may downregulate MHC class I expression on infected cells to avoid elimination by cytotoxic T cells. We report that the accessory proteins ORF7a and ORF3a of SARS-CoV-2 mediate this function and delineate the two distinct mechanisms involved. While ORF3a inhibits global protein trafficking to the cell surface, ORF7a acts specifically on MHC-I by competing with β[SUB]2[/SUB]m for binding to the MHC-I heavy chain. This is the first account of molecular mimicry of β[SUB]2[/SUB]m as a viral mechanism of MHC-I downregulation to facilitate immune evasion.
Abstract
Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small-protein β[SUB]2[/SUB]-microglobulin (β[SUB]2[/SUB]m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells, these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8[SUP]+[/SUP] T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that down-regulate MHC-I expression to avoid CD8[SUP]+[/SUP] T cell recognition. Here, we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, down-regulate MHC-I expression using distinct mechanisms. First, ORF3a, a viroporin, reduces the global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of β[SUB]2[/SUB]m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a specific mechanism that allows immune evasion by SARS-CoV-2.
https://www.pnas.org/doi/10.1073/pnas.2208525120
https://doi.org/10.1073/pnas.2208525120
Najla Arshad, Maudry Laurent-Rolle, Wesam S. Ahmed, Jack Chun-Chieh Hsu, Susan M. Mitchell, Joanna Pawlak, Debrup Sengupta, Kabir H. Biswas, and Peter Cresswell
Significance
Viruses may downregulate MHC class I expression on infected cells to avoid elimination by cytotoxic T cells. We report that the accessory proteins ORF7a and ORF3a of SARS-CoV-2 mediate this function and delineate the two distinct mechanisms involved. While ORF3a inhibits global protein trafficking to the cell surface, ORF7a acts specifically on MHC-I by competing with β[SUB]2[/SUB]m for binding to the MHC-I heavy chain. This is the first account of molecular mimicry of β[SUB]2[/SUB]m as a viral mechanism of MHC-I downregulation to facilitate immune evasion.
Abstract
Major histocompatibility complex class I (MHC-I) molecules, which are dimers of a glycosylated polymorphic transmembrane heavy chain and the small-protein β[SUB]2[/SUB]-microglobulin (β[SUB]2[/SUB]m), bind peptides in the endoplasmic reticulum that are generated by the cytosolic turnover of cellular proteins. In virus-infected cells, these peptides may include those derived from viral proteins. Peptide-MHC-I complexes then traffic through the secretory pathway and are displayed at the cell surface where those containing viral peptides can be detected by CD8[SUP]+[/SUP] T lymphocytes that kill infected cells. Many viruses enhance their in vivo survival by encoding genes that down-regulate MHC-I expression to avoid CD8[SUP]+[/SUP] T cell recognition. Here, we report that two accessory proteins encoded by SARS-CoV-2, the causative agent of the ongoing COVID-19 pandemic, down-regulate MHC-I expression using distinct mechanisms. First, ORF3a, a viroporin, reduces the global trafficking of proteins, including MHC-I, through the secretory pathway. The second, ORF7a, interacts specifically with the MHC-I heavy chain, acting as a molecular mimic of β[SUB]2[/SUB]m to inhibit its association. This slows the exit of properly assembled MHC-I molecules from the endoplasmic reticulum. We demonstrate that ORF7a reduces antigen presentation by the human MHC-I allele HLA-A*02:01. Thus, both ORF3a and ORF7a act post-translationally in the secretory pathway to lower surface MHC-I expression, with ORF7a exhibiting a specific mechanism that allows immune evasion by SARS-CoV-2.
https://www.pnas.org/doi/10.1073/pnas.2208525120