SARS-CoV-2 ORF8: One protein, seemingly one structure, and many functions

Abstract

SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. The genome of SARS-CoV-2 encodes nine accessory proteins that are involved in host-pathogen interaction. ORF8 is unique among these accessory proteins. SARS-CoV-2 ORF8 shares a surprisingly low amino acid sequence similarity with SARS-COV ORF8 (30%), and it is presumed to have originated from bat. Studies have shown that ORF8 exerts multiple different functions that interfere with host immune responses, including the downregulation of MHC class I molecules. These functions may represent strategies of host immune evasion. The x-ray crystal structure of ORF8 revealed an immunoglobulin-like domain with several distinguishing features. To date, there are numerous unanswered questions about SARS-CoV-2 ORF8 protein and its structure-function relationship that we discuss in this mini-review. A better understanding of how ORF8 interacts with components of the immune system is needed for elucidating COVID-19 pathogenesis and to develop new avenues for the treatment of the disease.

Consensus insertion/deletions and amino acid variations of all coding and noncoding regions of the SARS-CoV-2 Omicron clades, including the XBB and BQ.1 lineages

“…Deletions in ORF7 and 8 have been associated with milder symptoms [ 23 ]. ORF8 interferes with host immune responses in various ways, including downregulating MHC class I molecules [ 24 ], antagonizing interferon [ 25 ], activating interleukin 17, and cytokine storms [ 26 ]. It is therefore reasonable to suggest that the truncated ORF8 is additional indirect evidence of lower virulence or attenuation, especially in clade 22E.…”

Consensus insertion/deletions and amino acid variations of all coding and noncoding regions of the SARS-CoV-2 Omicron clades, including the XBB and BQ.1 lineages

“…The deletions of ORF7 and 8 have been associated with milder symptoms [23]. ORF8 interferes with host immune responses by, among many disturbances, downregulating MHC class I molecules [24], antagonizing interferon [25], and activating interleukin 17 and cytokine storms [26]. Therefore, it is reasonable to suggest that the truncated ORF8 is additional indirect evidence of lower virulence or attenuation, especially in clade 22E.…”

COVID‐19‐induced autoimmune thyroiditis: Exploring molecular mechanisms

“…Meanwhile, these short-term autoantibodies may arise as a consequence of bystander activation or molecular mimicry, where viral antigens share structural similarities with self-antigens. 58 Furthermore, The accessory proteins of the virus could trigger autoimmunity via cytokine signaling pathways and apoptosis; for example, ORF3a has been reported to induce the expression of IL-1β and activation of caspase 3, leading to cell apoptosis 59 ; ORF8 can bind to IL-17RA on monocytes and significantly promote inflammation 60 ; and ORF9c can induce IL-6 signaling pathways 61,62 Meanwhile, HLA-DRB1*04:06 is found to be a risk factor for probable autoimmune disorder. 63 Besides, HLA-DQA1 and HLA-DRB1 are linked with IL-6 involving in disease severity 63 and HLA-DRB1 has been associated with autoimmune thyroiditis.…”

“…Furthermore, The accessory proteins of the virus could trigger autoimmunity via cytokine signaling pathways and apoptosis; for example, ORF3a has been reported to induce the expression of IL‐1β and activation of caspase 3, leading to cell apoptosis 59 ; ORF8 can bind to IL‐17RA on monocytes and significantly promote inflammation 60 ; and ORF9c can induce IL‐6 signaling pathways 61,62 and likely contributes to the cytokine storm.…”