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Lost in deletion: The enigmatic ORF8 protein of SARS-CoV-2.

ABSTRACT: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome contains nine open reading frames (ORFs) that encode for accessory proteins which, although dispensable for viral replication, are important for the modulation of the host infected cell metabolism and innate immunity evasion. Among those, the ORF8 gene encodes for the homonymous multifunctional, highly immunogenic, immunoglobulin-like protein that was recently found to inhibit presentation of viral antigens by class I major histocompatibility complex, suppress the type I interferon antiviral response and interact with host factors involved in pulmonary inflammation and fibrogenesis. Moreover, the ORF8 is a hypervariable gene rapidly evolving among SARS-related coronaviruses, with a tendency to recombine and undergo deletions that are deemed to facilitate the virus adaptation to the human host. Intriguingly, SARS-CoV-2 variants isolated in the beginning of the coronavirus disease 2019 (Covid-19) pandemic that were deleted of the ORF8 gene have been associated to milder symptoms and better disease outcome. This minireview summarizes the current knowledge on the SARS-CoV-2 ORF8 protein in perspective to its potential as antiviral target and with special emphasis on the biochemical, biophysical and structural aspects of its molecular biology.

SUBMITTER: Zinzula L

PROVIDER: S-EPMC7577707 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Lost in deletion: The enigmatic ORF8 protein of SARS-CoV-2.

Zinzula Luca L

Biochemical and biophysical research communications 20201021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome contains nine open reading frames (ORFs) that encode for accessory proteins which, although dispensable for viral replication, are important for the modulation of the host infected cell metabolism and innate immunity evasion. Among those, the ORF8 gene encodes for the homonymous multifunctional, highly immunogenic, immunoglobulin-like protein that was recently found to inhibit presentation of viral antigens by class I major ...[more]

PMID: 33685621

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Project description:As the world continues to fight the coronavirus pandemic caused by SARS‐CoV‐2, we are gaining valuable insights by comparing this virus to other human coronaviruses such as SARS‐CoV and MERS‐CoV that have also caused outbreaks. Coronaviruses infect many animal species, but disease severity varies between strains. Viral accessory proteins are generally implicated in increased infectivity, pathogenicity, and virulence. The accessory protein open reading frame 8 (ORF8), although not essential for viral replication, appears to play a critical role in disease severity by inhibiting multiple pathways of the immune response. Furthermore, the ORF8 gene is found within a highly variable portion of the genome, increasing the possibility of dangerous mutant forms arising. Structure‐based design of therapeutics holds great promise for effective targeting of such rapidly evolving threats. Thus, we designed physical models and computer representations of ORF8, based on the published structure 7JTL, to better evaluate the structural features responsible for viral pathogenicity. ORF8 exists as a homodimer held together by amino acid residues that interact through hydrophobic interactions, hydrogen bonding, a salt bridge, and a disulfide bond. These interactions occur in a region referred to as the covalent interface. Another interface, referred to as the noncovalent interface, exists between separate homodimers and results in oligomerization. The homodimers in the oligomer are held together by an intermolecular beta sheet that is stabilized by an extensive hydrophobic surface. These two dimerization interfaces are unique to SARS‐CoV‐2 and have been proposed to be involved in the protein's ability to evade and suppress the host immune response. The computer and physical representations allow for better visualization of the ORF8 structure to evaluate the role of the multimeric structure. ORF8 has been found to interact with various host proteins, including Interleukin‐17 Receptor A (IL17RA), a pro‐inflammatory cytokine. To further corroborate the existence of this interaction and to better understand the role oligomerization might play in pathogenicity, we assessed the possible interactions of ORF8 (7JTL) and IL17RA (5N9B) through theoretical modeling using available tools such as HDOCK. A better understanding of these inter‐subunit interactions may improve our understanding of the unique mechanism the virus uses to evade the immune system and may be instrumental in the development of effective therapeutics.

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Lost in deletion: The enigmatic ORF8 protein of SARS-CoV-2.

Publications

Lost in deletion: The enigmatic ORF8 protein of SARS-CoV-2.

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