ORF7a (also known by several other names, including SARS coronavirus X4, SARS-X4, ORF7a, or U122) is a

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

found in

coronavirus Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the comm ...

es of the ''

Betacoronavirus ''Betacoronavirus'' (β-CoVs or Beta-CoVs) is one of four genera (''Alphacoronavirus, Alpha''-, ''Beta-'', ''Gammacoronavirus, Gamma-'', and ''Deltacoronavirus (genus), Delta-'') of coronaviruses. Member viruses are Viral envelope, enveloped, p ...

genus Genus (; : genera ) is a taxonomic rank above species and below family (taxonomy), family as used in the biological classification of extant taxon, living and fossil organisms as well as Virus classification#ICTV classification, viruses. In bino ...

. It expresses the Betacoronavirus NS7A protein, a

type I transmembrane protein A single-pass membrane protein also known as single-spanning protein or bitopic protein is a transmembrane protein that spans the lipid bilayer only once. These proteins may constitute up to 50% of all transmembrane proteins, depending on the or ...

with an

immunoglobulin An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

-like

protein domain In molecular biology, a protein domain is a region of a protein's Peptide, polypeptide chain that is self-stabilizing and that Protein folding, folds independently from the rest. Each domain forms a compact folded Protein tertiary structure, thre ...

. It was first discovered in SARS-CoV, the virus that causes

severe acute respiratory syndrome Severe acute respiratory syndrome (SARS) is a viral respiratory disease of zoonotic origin caused by the virus SARS-CoV-1, the first identified strain of the SARS-related coronavirus. The first known cases occurred in November 2002, and the sy ...

(SARS). The

homolog In biology, homology is similarity in anatomical structures or genes between organisms of different taxa due to shared ancestry, ''regardless'' of current functional differences. Evolutionary biology explains homologous structures as retained her ...

SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19, the respiratory illness responsible for the COVID-19 pandemic. The virus previously had the Novel coronavirus, provisional nam ...

, the virus that causes

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...

, has about 85% sequence identity to the SARS-CoV protein.

Function

A number of possible functions for the ORF7a protein have been described. The primary function is thought to be immunomodulation and

interferon Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten ...

antagonism. The protein is not essential for

viral replication Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome ...

Viral protein interactions

Studies in SARS-CoV suggest that the protein forms protein-protein interactions with

spike protein In virology, a spike protein or peplomer protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an viral envelope, enveloped virus. as cited in The proteins are usually glycoproteins that ...

and

ORF3a ORF3a (previously known as X1 or U274) is a gene found in coronaviruses of the subgenus ''Sarbecovirus'', including SARS-CoV and SARS-CoV-2. It encodes an accessory protein about 275 amino acid residues long, which is thought to function as a ...

, and is present in mature

virion A virion (plural, ''viria'' or ''virions'') is an inert virus particle capable of invading a Cell (biology), cell. Upon entering the cell, the virion disassembles and the genetic material from the virus takes control of the cell infrastructure, t ...

s, making it a minor viral structural protein. It is unclear if this occurs in SARS-CoV-2. It may have a role in viral assembly.

Host effects

A number of interactions with host proteins and effects on

host cell In biology and medicine, a host is a larger organism that harbours a smaller organism; whether a parasitic, a mutualistic, or a commensalist ''guest'' (symbiont). The guest is typically provided with nourishment and shelter. Examples include ...

processes have been described. The SARS-CoV ORF7a protein has been reported to have binding activity to

integrin Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...

I domains. It has also been reported to induce

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

via a

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyste ...

dependent pathway. Also, it contains a motif which has been demonstrated to mediate

COPII The coat protein complex II, or COPII, is a group of proteins that facilitate the formation of vesicles to transport proteins from the endoplasmic reticulum to the Golgi apparatus or endoplasmic-reticulum–Golgi intermediate compartment. Thi ...

dependent transport out of the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

, and the protein is targeted to the Golgi apparatus. In SARS-CoV-2, ORF7a protein has been described as an effective

antagonist. The SARS-CoV-2 protein may have immunomodulatory effects through interaction with

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and monocyte-derived dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

Structure

The ORF7a protein is a

transmembrane protein A transmembrane protein is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequently un ...

with 121

amino acid residue In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

s in SARS-CoV-2 and 122 in SARS-CoV. It is a type I

with an

N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...

, an

ectodomain An ectodomain is the domain of a membrane protein that extends into the extracellular space (the space outside a cell). Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A n ...

that has an immunoglobulin fold, and a

C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When t ...

retention signal sequence. The structure contains seven beta strands which form two beta sheets, arranged in a beta sandwich. Most of the sequence differences between SARS-CoV and SARS-CoV-2 occur in the Ig-like ectodomain and may produce differences in protein-protein interactions.

Post-translational modifications

The SARS-CoV-2 ORF7a protein has been reported to be post-translationally modified by

ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

. Polyubiquitin chains attached to

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...

119 may be related to the protein's reported

antagonism.

Expression and localization

Along with the genes for other viral accessory proteins, the ORF7a gene is located near those encoding the viral structural proteins, at the 5' end of the coronavirus RNA genome. ORF7a is an overlapping gene that overlaps ORF7b. In SARS-CoV, subcellular localization to the

Golgi apparatus The Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic Cell (biology), cells. Part of the endomembrane system in the cytoplasm, it protein targeting, packages proteins ...

, and ERGIC has been reported, with similar Golgi localization described for SARS-CoV-2.

Evolution

It is thought that ''

ORF8 ORF8 is a gene that encodes a viral accessory protein, Betacoronavirus NS8 protein, in coronaviruses of the subgenus ''Sarbecovirus''. It is one of the least well conserved and most variable parts of the genome. In some viruses, a deletion spl ...

'' in SARS-CoV-2, which encodes a protein with a similar Ig-like fold, may be a

paralog Sequence homology is the biological homology between DNA, RNA, or protein sequences, defined in terms of shared ancestry in the evolutionary history of life. Two segments of DNA can have shared ancestry because of three phenomena: either a sp ...

of ORF7a that originated through

gene duplication Gene duplication (or chromosomal duplication or gene amplification) is a major mechanism through which new genetic material is generated during molecular evolution. It can be defined as any duplication of a region of DNA that contains a gene ...

, though some

bioinformatics Bioinformatics () is an interdisciplinary field of science that develops methods and Bioinformatics software, software tools for understanding biological data, especially when the data sets are large and complex. Bioinformatics uses biology, ...

analyses suggest the similarity may be too low to support duplication, which is relatively uncommon in viruses. Immunoglobulin domains are uncommon in coronaviruses; other than the subset of

betacoronavirus ''Betacoronavirus'' (β-CoVs or Beta-CoVs) is one of four genera (''Alphacoronavirus, Alpha''-, ''Beta-'', ''Gammacoronavirus, Gamma-'', and ''Deltacoronavirus (genus), Delta-'') of coronaviruses. Member viruses are Viral envelope, enveloped, p ...

es with ORF8 and ORF7a, only a small number of bat

alphacoronavirus Alphacoronaviruses (Alpha-CoV) are members of the first of the four genera (''Alpha''-, '' Beta-'', '' Gamma-'', and '' Delta-'') of coronaviruses. They are positive-sense, single-stranded RNA viruses that infect mammals, including humans. They ...

es have been identified as containing likely Ig domains, while they are absent from

gammacoronavirus ''Gammacoronavirus'' (Gamma-CoV) is one of the four genera (''Alphacoronavirus, Alpha''-, ''Betacoronavirus, Beta-'', ''Gamma-'', and ''Deltacoronavirus (genus), Delta-'') of coronaviruses. It is in the subfamily ''Orthocoronavirinae'' of the fa ...

es and deltacoronaviruses. The beta and alpha Ig domains may be independent acquisitions, where ORF8 and ORF7a may have been acquired from host proteins. Many SARS-CoV-2 genomes have been sequenced throughout the

COVID-19 pandemic The COVID-19 pandemic (also known as the coronavirus pandemic and COVID pandemic), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began with an disease outbreak, outbreak of COVID-19 in Wuhan, China, in December ...

and a number of variations have been reported, including deletion mutations,

nonsense mutation In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a ''nonsense codon'', or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. No ...

s (introducing a premature

stop codon In molecular biology, a stop codon (or termination codon) is a codon (nucleotide triplet within messenger RNA) that signals the termination of the translation process of the current protein. Most codons in messenger RNA correspond to the additio ...

and truncating the protein), and at least one

gene fusion In genetics, a fusion gene is a hybrid gene formed from two previously independent genes. It can occur as a result of translocation, interstitial deletion, or chromosomal inversion. Fusion genes have been found to be prevalent in all main types ...

. Recent analyses indicate that the repeated knockout of ORF8 in SARS-CoV-2 through deletion mutations is driven by positive selection, suggesting an adaptive advantage for the virus during human infection. The study showed ORF8 deletions were associated with less severe clinical disease.

References

{{Viral proteins Protein domains Coronavirus proteins