ORF3b is agene found incoronaviruses of thesubgenusSarbecovirus, encoding a shortnon-structuralprotein. It is present in bothSARS-CoV (which causes the diseaseSARS) andSARS-CoV-2 (which causesCOVID-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 22amino 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 asinterferon antagonists.^[2] It is unclear whether the SARS-CoV-2 gene expresses a functional protein.^[3]

There has been significant confusion in the scientific literature around the nomenclature used for theaccessory proteins ofSARS-CoV-2, especially severaloverlapping genes withORF3a.^[1] Due to differences in the genomes ofSARS-CoV and SARS-CoV-2, two distinctopen reading frames (ORFs) in the SARS-CoV-2 genome have been referred to as "ORF3b". In SARS-CoV, ORF3b is a gene of 155codons. In SARS-CoV-2, thehomologous region of the genome includes severalstop codons in the samereading 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 asinterferon 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 termORF3b for the 22-codon gene homologous to the5' end of ORF3b in SARS-CoV. The termORF3c is used for the 41-codon gene and the termORF3d is used for the 57-codon gene.^[1]

Like other genes encoding accessory proteins, ORF3b is located in thegenome near the genes encodingviral structural proteins. It is one of severaloverlapping genes in this region of the genome, overlappingORF3a and, inSARS-CoV, the E gene encoding theenvelope 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 theSarbecovirussubgenus with significant length variations among known related viruses.^[2] Its sequence is not wellconserved within theSARSr-CoV species.^[3]

In SARS-CoV, the ORF3b protein istranslated through aninternal ribosome entry site (IRES).^[8] It has anuclear localization signal at theC-terminus and has beenlocalized to thenucleolus andmitochondria.^[8] It is notessential forviral replication.^[8]

In SARS-CoV-2, it is unclear if ORF3b is functional.Proteomics studies,RNA sequencing ofsubgenomic RNA,ribosome profiling, andcomparative genomics have all been used to examine the functional gene content of SARS-CoV-2 and found little evidence that ORF3bexpresses a functional protein.^[3] The SARS-CoV-2 protein has been reported to localize primarily to thecytosol 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]

In SARS-CoV, ORF3b has been reported to induceG0/G1cell cycle arrest andapoptosis when studied incell culture.^[8][9]

In SARS-CoV, ORF3b has been described as aninterferon antagonist, suppressing thetype I interferon response through inhibition ofIRF3.^[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]

In SARS-CoV, ORF3b protein reportedly activates thetranscription factorAP-1 through theJNK andERKsignaling pathways.^[10][8]

• Viral nonstructural proteins
• Coronavirus proteins

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