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. Both the longer SARS-CoV and shorter SARS-CoV-2 proteins have been reported as interferon antagonists. It is unclear whether the SARS-CoV-2 gene expresses a functional protein.
20-472: 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 . 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,
40-403: A JNK signaling pathway causing apoptosis of developing neurons. JNK, through a series of intermediates, activates p53 and p53 activates Bax which initiates apoptosis. TrkA can prevent p75NTR-mediated JNK pathway apoptosis. JNK can directly phosphorylate Bim-EL, a splicing isoform of Bcl-2 interacting mediator of cell death (Bim) , which activates Bim-EL apoptotic activity. JNK activation
60-417: Is a type of viral protein that can play an indirect role in the function of a virus. An example is Nef . This virus -related article is a stub . You can help Misplaced Pages by expanding it . JNK c-Jun N-terminal kinases ( JNKs ), were originally identified as kinases that bind and phosphorylate c-Jun on Ser -63 and Ser-73 within its transcriptional activation domain. They belong to
80-413: Is carried out by two MAP kinase kinases, MKK4 and MKK7 , and JNK can be inactivated by Ser/Thr and Tyr protein phosphatases . It has been suggested that this signaling pathway contributes to inflammatory responses in mammals and insects. The c-Jun N-terminal kinases consist of ten isoforms derived from three genes: JNK1 (four isoforms), JNK2 (four isoforms) and JNK3 (two isoforms). Each gene
100-439: Is expressed as either 46 kDa or 55 kDa protein kinases, depending upon how the 3' coding region of the corresponding mRNA is processed. There have been no functional differences documented between the 46 kDa and the 55 kDa isoform, however, a second form of alternative splicing occurs within transcripts of JNK1 and JNK2, yielding JNK1-α, JNK2-α and JNK1-β and JNK2-β. Differences in interactions with protein substrates arise because of
120-406: Is involved in apoptosis , neurodegeneration , cell differentiation and proliferation, inflammatory conditions and cytokine production mediated by AP-1 ( activation protein 1 ) such as RANTES , IL-8 and GM-CSF . Recently, JNK1 has been found to regulate Jun protein turnover by phosphorylation and activation of the ubiquitin ligase Itch . Neurotrophin binding to p75NTR activates
140-534: 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 . Its length varies significantly, from 22 amino acids in SARS-CoV-2 to around 155 residues in SARS-CoV, with other related bat coronaviruses exhibiting intermediate truncations of varying lengths. It
160-416: Is not essential for viral replication . 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. The SARS-CoV-2 protein has been reported to localize primarily to
180-511: Is required for apoptosis but c-jun , a protein involved in the JNK pathway, is not always required. The packaging of eukaryotic DNA into chromatin presents a barrier to all DNA-based processes that require recruitment of enzymes to their sites of action. To allow repair of double-strand breaks in DNA, the chromatin must be remodeled. Chromatin relaxation occurs rapidly at the site of a DNA damage. In one of
200-612: Is the only ORF in the Sarbecovirus subgenus with significant length variations among known related viruses. Its sequence is not well conserved within the SARSr-CoV species. In SARS-CoV, the ORF3b protein is translated through an internal ribosome entry site (IRES). It has a nuclear localization signal at the C-terminus and has been localized to the nucleolus and mitochondria . It
220-512: Is usually known to function in microRNA biogenesis, the microRNA-generating activity of DGCR8 is not required for DGCR8-dependent removal of UV-induced photoproducts. Nucleotide excision repair is also needed for repair of oxidative DNA damage due to hydrogen peroxide ( H 2 O 2 ), and DGCR8 depleted cells are sensitive to H 2 O 2 . In Drosophila , flies with mutations that augment JNK signaling accumulate less oxidative damage and live dramatically longer than wild-type flies. In
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#1732898987232240-461: The cytosol when expressed in cell culture. Truncated forms of the protein from bat coronaviruses are also reportedly cytosolic, likely due to loss of the C-terminal nuclear localization sequence. In SARS-CoV, ORF3b has been reported to induce G0 / G1 cell cycle arrest and apoptosis when studied in cell culture . In SARS-CoV, ORF3b has been described as an interferon antagonist, suppressing
260-414: 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. Exacerbating the confusion, both the 57-codon protein product and the 22-codon protein product have been described to have similar effects as interferon antagonists. In addition,
280-474: The mitogen-activated protein kinase family, and are responsive to stress stimuli, such as cytokines , ultraviolet irradiation, heat shock, and osmotic shock. They also play a role in T cell differentiation and the cellular apoptosis pathway. Activation occurs through a dual phosphorylation of threonine (Thr) and tyrosine (Tyr) residues within a Thr- Pro -Tyr motif located in kinase subdomain VIII. Activation
300-539: The type I interferon response through inhibition of IRF3 . 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. In SARS-CoV, ORF3b protein reportedly activates the transcription factor AP-1 through the JNK and ERK signaling pathways . Accessory protein A viral regulatory and accessory protein
320-771: The activity of JNK itself and the activity of proteins linked to JNK activation. JNKs can associate with scaffold proteins JNK interacting proteins (JIP) as well as their upstream kinases JNKK1 and JNKK2 following their activation. JNK, by phosphorylation, modifies the activity of numerous proteins that reside at the mitochondria or act in the nucleus. Downstream molecules that are activated by JNK include c-Jun , ATF2 , ELK1 , SMAD4 , p53 and HSF1 . The downstream molecules that are inhibited by JNK activation include NFAT4 , NFATC1 and STAT3 . By activating and inhibiting other small molecules in this way, JNK activity regulates several important cellular functions including cell growth, differentiation, survival and apoptosis. JNK1
340-516: The damage occurs. The chromatin remodeler Alc1 quickly attaches to the product of PARP1 action, a poly-ADP ribose chain, allowing half of the maximum chromatin relaxation, presumably due to action of Alc1, by 10 seconds. This allows recruitment of the DNA repair enzyme MRE11 , to initiate DNA repair, within 13 seconds. Removal of UV-induced DNA photoproducts , during transcription coupled nucleotide excision repair (TC-NER) , depends on JNK phosphorylation of DGCR8 on serine 153. While DGCR8
360-454: The earliest steps, JNK phosphorylates SIRT6 on serine 10 in response to double-strand breaks (DSBs) or other DNA damage, and this step is required for efficient repair of DSBs. Phosphorylation of SIRT6 on S10 facilitates the mobilization of SIRT6 to DNA damage sites, where SIRT6 then recruits and mono-phosphorylates poly (ADP-ribose) polymerase 1 ( PARP1 ) at DNA break sites. Half maximum accumulation of PARP1 occurs within 1.6 seconds after
380-485: The mutually exclusive utilization of two exons within the kinase domain. c-Jun N-terminal kinase isoforms have the following tissue distribution: Inflammatory signals, changes in levels of reactive oxygen species , ultraviolet radiation, protein synthesis inhibitors, and a variety of stress stimuli can activate JNK. One way this activation may occur is through disruption of the conformation of sensitive protein phosphatase enzymes; specific phosphatases normally inhibit
400-464: The putative product of yet a third ORF of 41 codons has at least once been described as "3b protein". Numerous publications on SARS-CoV-2 refer ambiguously to "ORF3b". 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. Like other genes encoding accessory proteins, ORF3b
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