ORF3b

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ORF3b
Identifiers
Organism SARS-CoV
SymbolORF3b
UniProt P59633
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Structures Swiss-model
Domains InterPro
ORF3b
Identifiers
Organism SARS-CoV-2
SymbolORF3b
UniProt P0DTF1
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Structures Swiss-model
Domains InterPro

ORF3b is a gene found in coronaviruses of the subgenus Sarbecovirus , encoding a short non-structural protein. It is present in both SARS-CoV (which causes the disease SARS) and SARS-CoV-2 (which causes COVID-19), though the protein product has very different lengths in the two viruses. The encoded protein is significantly shorter in SARS-CoV-2, at only 22 amino acid residues compared to 153–155 in SARS-CoV. [1] [2] Both the longer SARS-CoV and shorter SARS-CoV-2 proteins have been reported as interferon antagonists. [2] It is unclear whether the SARS-CoV-2 gene expresses a functional protein. [3]

Contents

Nomenclature

There has been significant confusion in the scientific literature around the nomenclature used for the accessory proteins of SARS-CoV-2, especially several overlapping genes with ORF3a. [1] Due to differences in the genomes of SARS-CoV and SARS-CoV-2, two distinct open reading frames (ORFs) in the SARS-CoV-2 genome have been referred to as "ORF3b". In SARS-CoV, ORF3b is a gene of 155 codons. In SARS-CoV-2, the homologous region of the genome includes several stop codons in the same reading frame, resulting in a truncated gene of 22 codons. As a result, some papers have used the term "ORF3b" to refer to a later ORF with 57 codons. [1] Exacerbating the confusion, both the 57-codon protein product [4] and the 22-codon protein product [2] have been described to have similar effects as interferon antagonists. [1] In addition, the putative product of yet a third ORF of 41 codons has at least once been described as "3b protein". [5] [1] Numerous publications on SARS-CoV-2 refer ambiguously to "ORF3b". [1]

The recommended nomenclature for SARS-CoV-2 uses the term ORF3b for the 22-codon gene homologous to the 5' end of ORF3b in SARS-CoV. The term ORF3c is used for the 41-codon gene and the term ORF3d is used for the 57-codon gene. [1]

Comparative genomics

Like other genes encoding accessory proteins, ORF3b is located in the genome near the genes encoding viral structural proteins. It is one of several overlapping genes in this region of the genome, overlapping ORF3a and, in SARS-CoV, the E gene encoding the envelope protein. [1] Its length varies significantly, from 22 amino acids in SARS-CoV-2 to around 155 residues in SARS-CoV, [1] with other related bat coronaviruses exhibiting intermediate truncations of varying lengths. [6] [7] It is the only ORF in the Sarbecovirus subgenus with significant length variations among known related viruses. [2] Its sequence is not well conserved within the SARSr-CoV species. [3]

Expression and localization

In SARS-CoV, the ORF3b protein is translated through an internal ribosome entry site (IRES). [8] It has a nuclear localization signal at the C-terminus and has been localized to the nucleolus and mitochondria. [8] It is not essential for viral replication. [8]

In SARS-CoV-2, it is unclear if ORF3b is functional. Proteomics studies, RNA sequencing of subgenomic RNA, ribosome profiling, and comparative genomics have all been used to examine the functional gene content of SARS-CoV-2 and found little evidence that ORF3b expresses a functional protein. [3] The SARS-CoV-2 protein has been reported to localize primarily to the cytosol when expressed in cell culture. [2] Truncated forms of the protein from bat coronaviruses are also reportedly cytosolic, likely due to loss of the C-terminal nuclear localization sequence. [7]

Function

Cell growth

In SARS-CoV, ORF3b has been reported to induce G0/G1 cell cycle arrest and apoptosis when studied in cell culture. [8] [9]

Interferon antagonist

In SARS-CoV, ORF3b has been described as an interferon antagonist, suppressing the type I interferon response through inhibition of IRF3. [8] Studies of the truncated SARS-CoV-2 ORF3b protein in cell culture suggest it is a more potent interferon antagonist than the SARS-CoV protein, which may be related to its length and to differences in subcellular localization. [2]

Effect on AP-1

In SARS-CoV, ORF3b protein reportedly activates the transcription factor AP-1 through the JNK and ERK signaling pathways. [10] [8]

Related Research Articles

<span class="mw-page-title-main">Coronavirus</span> Subfamily of viruses in the family Coronaviridae

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 common cold, while more lethal varieties can cause SARS, MERS and COVID-19, which is causing the ongoing pandemic. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis.

<span class="mw-page-title-main">SARS-related coronavirus</span> Species of coronavirus causing SARS and COVID-19

Severe acute respiratory syndrome–related coronavirus is a species of virus consisting of many known strains phylogenetically related to severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) that have been shown to possess the capability to infect humans, bats, and certain other mammals. These enveloped, positive-sense single-stranded RNA viruses enter host cells by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. The SARSr-CoV species is a member of the genus Betacoronavirus and of the subgenus Sarbecovirus.

<i>Nidovirales</i> Order of positive-sense, single-stranded RNA viruses

Nidovirales is an order of enveloped, positive-strand RNA viruses which infect vertebrates and invertebrates. Host organisms include mammals, birds, reptiles, amphibians, fish, arthropods, molluscs, and helminths. The order includes the families Coronaviridae, Arteriviridae, Roniviridae, and Mesoniviridae.

<i>Murine coronavirus</i> Species of virus

Murine coronavirus (M-CoV) is a virus in the genus Betacoronavirus that infects mice. Belonging to the subgenus Embecovirus, murine coronavirus strains are enterotropic or polytropic. Enterotropic strains include mouse hepatitis virus (MHV) strains D, Y, RI, and DVIM, whereas polytropic strains, such as JHM and A59, primarily cause hepatitis, enteritis, and encephalitis. Murine coronavirus is an important pathogen in the laboratory mouse and the laboratory rat. It is the most studied coronavirus in animals other than humans, and has been used as an animal disease model for many virological and clinical studies.

<span class="mw-page-title-main">ORF7a</span> Gene found in coronaviruses of the Betacoronavirus genus

ORF7a is a gene found in coronaviruses of the Betacoronavirus genus. It expresses the Betacoronavirus NS7A protein, a type I transmembrane protein with an immunoglobulin-like protein domain. It was first discovered in SARS-CoV, the virus that causes severe acute respiratory syndrome (SARS). The homolog in SARS-CoV-2, the virus that causes COVID-19, has about 85% sequence identity to the SARS-CoV protein.

An overlapping gene is a gene whose expressible nucleotide sequence partially overlaps with the expressible nucleotide sequence of another gene. In this way, a nucleotide sequence may make a contribution to the function of one or more gene products. Overlapping genes are present in and a fundamental feature of both cellular and viral genomes. The current definition of an overlapping gene varies significantly between eukaryotes, prokaryotes, and viruses. In prokaryotes and viruses overlap must be between coding sequences but not mRNA transcripts, and is defined when these coding sequences share a nucleotide on either the same or opposite strands. In eukaryotes, gene overlap is almost always defined as mRNA transcript overlap. Specifically, a gene overlap in eukaryotes is defined when at least one nucleotide is shared between the boundaries of the primary mRNA transcripts of two or more genes, such that a DNA base mutation at any point of the overlapping region would affect the transcripts of all genes involved. This definition includes 5′ and 3′ untranslated regions (UTRs) along with introns.

<i>Embecovirus</i> Subgenus of viruses

Embecovirus is a subgenus of coronaviruses in the genus Betacoronavirus. The viruses in this subgenus, unlike other coronaviruses, have a hemagglutinin esterase (HE) gene. The viruses in the subgenus were previously known as group 2a coronaviruses.

ORF3d is a gene found in SARS-CoV-2 and at least one closely related coronavirus found in pangolins, though it is not found in other closely related viruses within the Sarbecovirus subgenus. It is 57 codons long and encodes a novel 57 amino acid residue protein of unknown function. At least two isoforms have been described, of which the shorter 33-residue form, ORF3d-2, may be more highly expressed, or even the only form expressed. It is reported to be antigenic and antibodies to the ORF3d protein occur in patients recovered from COVID-19. There is no homolog in the genome of the otherwise closely related SARS-CoV.

<span class="mw-page-title-main">Coronavirus membrane protein</span> Major structure in coronaviruses

The membrane (M) protein is an integral membrane protein that is the most abundant of the four major structural proteins found in coronaviruses. The M protein organizes the assembly of coronavirus virions through protein-protein interactions with other M protein molecules as well as with the other three structural proteins, the envelope (E), spike (S), and nucleocapsid (N) proteins.

<span class="mw-page-title-main">Coronavirus nucleocapsid protein</span> Most expressed structure in coronaviruses

The nucleocapsid (N) protein is a protein that packages the positive-sense RNA genome of coronaviruses to form ribonucleoprotein structures enclosed within the viral capsid. The N protein is the most highly expressed of the four major coronavirus structural proteins. In addition to its interactions with RNA, N forms protein-protein interactions with the coronavirus membrane protein (M) during the process of viral assembly. N also has additional functions in manipulating the cell cycle of the host cell. The N protein is highly immunogenic and antibodies to N are found in patients recovered from SARS and COVID-19.

ORF3c is a gene found in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It was first identified in the SARS-CoV-2 genome and encodes a 41 amino acid non-structural protein of unknown function. It is also present in the SARS-CoV genome, but was not recognized until the identification of the SARS-CoV-2 homolog.

<span class="mw-page-title-main">ORF3a</span> Gene found in coronaviruses of the subgenus Sarbecovirus

ORF3a 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 viroporin. It is the largest accessory protein and was the first of the SARS-CoV accessory proteins to be described.

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.

<span class="mw-page-title-main">ORF8</span> Gene that encodes a viral accessory protein

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 splits the region into two smaller open reading frames, called ORF8a and ORF8b - a feature present in many SARS-CoV viral isolates from later in the SARS epidemic, as well as in some bat coronaviruses. For this reason the full-length gene and its protein are sometimes called ORF8ab. The full-length gene, exemplified in SARS-CoV-2, encodes a protein with an immunoglobulin domain of unknown function, possibly involving interactions with the host immune system. It is similar in structure to the ORF7a protein, suggesting it may have originated through gene duplication.

ORF6 is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is not present in MERS-CoV. It is thought to reduce the immune system response to viral infection through interferon antagonism.

<span class="mw-page-title-main">ORF9b</span> Gene

ORF9b is a gene that encodes a viral accessory protein in coronaviruses of the subgenus Sarbecovirus, including SARS-CoV and SARS-CoV-2. It is an overlapping gene whose open reading frame is entirely contained within the N gene, which encodes coronavirus nucleocapsid protein. The encoded protein is 97 amino acid residues long in SARS-CoV and 98 in SARS-CoV-2, in both cases forming a protein dimer.

ORF9c is an open reading frame (ORF) in coronavirus genomes of the subgenus Sarbecovirus. It is 73 codons long in the SARS-CoV-2 genome. Although it is often included in lists of Sarbecovirus viral accessory protein genes, experimental and bioinformatics evidence suggests ORF9c may not be a functional protein-coding gene.

ORF10 is an open reading frame (ORF) found in the genome of the SARS-CoV-2 coronavirus. It is 38 codons long. It is not conserved in all Sarbecoviruses. In studies prompted by the COVID-19 pandemic, ORF10 attracted research interest as one of two viral accessory protein genes not conserved between SARS-CoV and SARS-CoV-2 and was initially described as a protein-coding gene likely under positive selection. However, although it is sometimes included in lists of SARS-CoV-2 accessory genes, experimental and bioinformatics evidence suggests ORF10 is likely not a functional protein-coding gene.

ORF1ab refers collectively to two open reading frames (ORFs), ORF1a and ORF1b, that are conserved in the genomes of nidoviruses, a group of viruses that includes coronaviruses. The genes express large polyproteins that undergo proteolysis to form several nonstructural proteins with various functions in the viral life cycle, including proteases and the components of the replicase-transcriptase complex (RTC). Together the two ORFs are sometimes referred to as the replicase gene. They are related by a programmed ribosomal frameshift that allows the ribosome to continue translating past the stop codon at the end of ORF1a, in a -1 reading frame. The resulting polyproteins are known as pp1a and pp1ab.

Planarian secretory cell nidovirus (PSCNV) is a virus of the species Planidovirus 1, a nidovirus notable for its extremely large genome. At 41.1 kilobases, it is the largest known genome of an RNA virus. It was discovered by inspecting the transcriptomes of the planarian flatworm Schmidtea mediterranea and is the first known RNA virus infecting planarians. It was first described in 2018.

References

  1. 1 2 3 4 5 6 7 8 9 Jungreis I, Nelson CW, Ardern Z, Finkel Y, Krogan NJ, Sato K, et al. (June 2021). "Conflicting and ambiguous names of overlapping ORFs in the SARS-CoV-2 genome: A homology-based resolution". Virology. 558: 145–151. doi:10.1016/j.virol.2021.02.013. hdl: 1721.1/130363 . PMC   7967279 . PMID   33774510.
  2. 1 2 3 4 5 6 Konno Y, Kimura I, Uriu K, Fukushi M, Irie T, Koyanagi Y, et al. (September 2020). "SARS-CoV-2 ORF3b Is a Potent Interferon Antagonist Whose Activity Is Increased by a Naturally Occurring Elongation Variant". Cell Reports. 32 (12): 108185. doi:10.1016/j.celrep.2020.108185. PMC   7473339 . PMID   32941788.
  3. 1 2 3 Jungreis I, Sealfon R, Kellis M (May 2021). "SARS-CoV-2 gene content and COVID-19 mutation impact by comparing 44 Sarbecovirus genomes". Nature Communications. 12 (1): 2642. Bibcode:2021NatCo..12.2642J. doi:10.1038/s41467-021-22905-7. hdl: 1721.1/130581 . PMC   8113528 . PMID   33976134.
  4. ↑ Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. (February 2020). "Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding". Lancet. 395 (10224): 565–574. doi:10.1016/S0140-6736(20)30251-8. PMC   7159086 . PMID   32007145.
  5. ↑ Pavesi A (July 2020). "New insights into the evolutionary features of viral overlapping genes by discriminant analysis". Virology. 546: 51–66. doi:10.1016/j.virol.2020.03.007. PMC   7157939 . PMID   32452417.
  6. ↑ Hu B, Zeng LP, Yang XL, Ge XY, Zhang W, Li B, et al. (November 2017). "Discovery of a rich gene pool of bat SARS-related coronaviruses provides new insights into the origin of SARS coronavirus". PLOS Pathogens. 13 (11): e1006698. doi: 10.1371/journal.ppat.1006698 . PMC   5708621 . PMID   29190287.
  7. 1 2 Zhou P, Li H, Wang H, Wang LF, Shi Z (February 2012). "Bat severe acute respiratory syndrome-like coronavirus ORF3b homologues display different interferon antagonist activities". The Journal of General Virology. 93 (Pt 2): 275–281. doi: 10.1099/vir.0.033589-0 . PMID   22012463.
  8. 1 2 3 4 5 6 Liu DX, Fung TS, Chong KK, Shukla A, Hilgenfeld R (September 2014). "Accessory proteins of SARS-CoV and other coronaviruses". Antiviral Research. 109: 97–109. doi:10.1016/j.antiviral.2014.06.013. PMC   7113789 . PMID   24995382.
  9. ↑ Yuan X, Shan Y, Zhao Z, Chen J, Cong Y (August 2005). "G0/G1 arrest and apoptosis induced by SARS-CoV 3b protein in transfected cells". Virology Journal. 2 (66): 66. doi: 10.1186/1743-422X-2-66 . PMC   1190220 . PMID   16107218.
  10. ↑ Varshney B, Lal SK (June 2011). "SARS-CoV accessory protein 3b induces AP-1 transcriptional activity through activation of JNK and ERK pathways". Biochemistry. 50 (24): 5419–5425. doi:10.1021/bi200303r. PMID   21561061.
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