ORF6 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 ...

that encodes a

viral accessory protein A viral regulatory and accessory protein is a type of viral protein The term viral protein refers to both the products of the genome of a virus and any host proteins incorporated into the viral particle. Viral proteins are grouped according to t ...

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

subgenus In biology, a subgenus ( subgenera) is a taxonomic rank directly below genus. In the International Code of Zoological Nomenclature, a subgeneric name can be used independently or included in a species name, in parentheses, placed between the ge ...

Sarbecovirus Severe acute respiratory syndrome–related coronavirus (SARSr-CoV or SARS-CoV'', Betacoronavirus pandemicum'')The terms ''SARSr-CoV'' and ''SARS-CoV'' are sometimes used interchangeably, especially prior to the discovery of SARS-CoV-2. This m ...

'', including

SARS-CoV Severe acute respiratory syndrome–related coronavirus (SARSr-CoV or SARS-CoV'', Betacoronavirus pandemicum'')The terms ''SARSr-CoV'' and ''SARS-CoV'' are sometimes used interchangeably, especially prior to the discovery of SARS-CoV-2. This m ...

and

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 ...

. It is not present in

MERS-CoV Middle East respiratory syndrome–related coronavirus (MERS-CoV, ''Betacoronavirus cameli'') or EMC/2012 ( HCoV-EMC/2012), is the virus that causes Middle East respiratory syndrome (MERS). It is a species of coronavirus which infects humans, ba ...

. It is thought to reduce the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

response to viral infection through

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.

Structure

The ORF6 protein is fairly small at 63

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 long in

and 61 in

. The ORF6 sequence is not well conserved and it has a relatively low

sequence identity In bioinformatics, a sequence alignment is a way of arranging the sequences of DNA, RNA, or protein to identify regions of similarity that may be a consequence of functional, structural, or evolutionary relationships between the sequences. Align ...

between the two viruses at about 66%. It has an

amphipathic In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...

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 ...

alpha helix An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...

that associates with the

membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...

, but is not 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 ...

. Its approximately 20-residue

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 ...

tail is

polar Polar may refer to: Geography * Geographical pole, either of the two points on Earth where its axis of rotation intersects its surface ** Polar climate, the climate common in polar regions ** Polar regions of Earth, locations within the polar circ ...

and extends into the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

, and contains signal sequences for

protein trafficking Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the cell. Proteins can be targeted to the inner space of an organelle, different intracellular m ...

Expression and localization

Like the genes for other accessory proteins, the ORF6 gene is located near those encoding the

structural proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

, at the 5' end of the coronavirus RNA genome. Along with

ORF7a ORF7a (also known by several other names, including SARS coronavirus X4, SARS-X4, ORF7a, or U122) is a gene found in coronaviruses of the ''Betacoronavirus'' genus. It expresses the Betacoronavirus NS7A protein, a type I transmembrane protein wi ...

ORF7b ORF7b is a gene found in coronaviruses of the genus ''Betacoronavirus'', which expresses the accessory protein Betacoronavirus NS7b protein. It is a short, highly hydrophobic transmembrane protein of unknown function. Structure ORF7b protein ...

, and

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 ...

, ORF6 is located between the

(M) and

nucleocapsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...

(N) genes. It is localized to 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

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 ...

, with studies in SARS-CoV-2 also indicating association with

vesicle Vesicle may refer to: ; In cellular biology or chemistry * Vesicle (biology and chemistry), a supramolecular assembly of lipid molecules, like a cell membrane * Synaptic vesicle ; In human embryology * Vesicle (embryology), bulge-like features ...

s such as

autophagosome An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, i ...

s and

lysosome A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

Function

The primary function of the ORF6 protein is thought to be

immunomodulation Immunomodulation is modulation (regulatory adjustment) of the immune system. It has natural and human-induced forms, and thus the word can refer to the following: * Homeostasis in the immune system, whereby the system self-regulates to adjust immun ...

and

antagonism. It 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 ...

, though its absence appears to reduce replication efficiency.

Viral protein interactions

Studies in

suggest that the ORF6 protein exhibits protein-protein interactions with another viral accessory protein,

ORF9b ORF9b (formerly sometimes called ORF13) is a gene that encodes a viral accessory protein in coronavirus Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory ...

protein. In SARS-CoV, but not in recombinant murine hepatitis virus, ORF6 protein has been detected in

virus-like particle Virus-like particles (VLPs) are molecules that closely resemble viruses, but are non-infectious because they contain no viral genetic material. They can be naturally occurring or synthesized through the individual expression of viral structural pro ...

s and 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, suggesting it can be a minor

viral structural protein A viral structural protein is a viral protein that is a structural component of the mature virus. Examples include the SARS coronavirus 3a and 7a accessory proteins. Bacteriophage T4 structural proteins During assembly of the bacteriophage (phag ...

Immune effects

The ORF6 protein from both SARS-CoV and SARS-CoV-2 is an

antagonist and thought to be involved in

immune evasion Antigenic escape, immune escape, immune evasion or escape mutation occurs when the immune system of a host, especially of a human being, is unable to respond to an infectious agent: the host's immune system is no longer able to recognize and elimi ...

. Several protein-protein interactions with

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 ...

proteins have been described to mediate this effect. It has been reported to inhibit

nuclear import Nuclear transport refers to the mechanisms by which molecules move across the nuclear membrane of a cell. The entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes (NPCs). Although small molecule ...

of the STAT

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

, inhibiting interferon activation. Studies of SARS-CoV report this may be mediated by binding of ORF6 protein to

karyopherin Karyopherins are protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme c ...

s. In SARS-CoV-2, the ORF6 protein reportedly interacts with

RAE1 mRNA export factor is a protein that in humans is encoded by the ''RAE1'' 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 transc ...

and

NUP98 Nuclear pore complex protein Nup98-Nup96 is a protein that in humans is encoded by the ''NUP98'' gene. Function Signal-mediated nuclear import and export proceed through the nuclear pore complex (NPC), which is composed of approximately 30 uni ...

, blocking karyopherin interactions.

References

{{Viral proteins Coronavirus proteins