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Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the largest single‐stranded RNA virus known to date. Its genome contains multiple accessory protein genes that act against host immune responses but are not required for progeny virus production. The functions of the accessory proteins in the viral life cycle have been examined, but their involvement in viral pathogenicity remains unclear. Here, we investigated the roles of the accessory proteins in viral immunopathogenicity. To this end, recombinant SARS‐CoV‐2 possessing nonsense mutations in the seven accessory protein open reading frames (ORFs) (ORF3a, ORF3b, ORF6, ORF7a, ORF8, ORF9b, and ORF10) was de novo generated using an early pandemic SARS‐CoV‐2 strain as a backbone. We confirmed that the resultant virus (termed ORF3–10 KO) did not express accessory proteins in infected cells and retained the desired mutations in the viral genome. In cell culture, the ORF3–10 KO virus exhibited similar virus growth kinetics as the parental virus. In hamsters, ORF3–10 KO virus infection resulted in mild weight loss and reduced viral replication in the oral cavity and lung tissue. ORF3–10 KO virus infection led to mild inflammation, indicating that an inability to evade innate immune sensing because of a lack of accessory proteins impairs virus growth in vivo and results in quick elimination from the body. Overall, we showed that SARS‐CoV‐2 accessory proteins are involved in immunopathogenicity. [ABSTRACT FROM AUTHOR]

Emerging variants enable the continuous spread of SARS‐CoV‐2 in humans. The factors contributing to behavioral differences in variants remain elusive despite associations with several Spike protein mutations. Exploring accessory proteins may provide a wider understanding of these differences since these proteins may affect viral processes that occur beyond infection. Various bioinformatics tools were utilized to identify significant accessory protein mutations and determine their structural and functional effects over time. The ViruClust web application was used to retrieve accessory protein amino acid sequences and determine mutation frequencies in these sequences across time. The structural and functional effects of the mutations were determined using Missense3D and PROVEAN, respectively. The accessory and Spike protein mutations were compared using mutation densities. Q57H and T151I of ORF3a; T21I and W27L of ORF6; G38V, V82A, and T120I of ORF7a; S31P and T40I of ORF7b; and R52I, C61F, and I121L of ORF8 were highly frequent in most variants of concern and were within known functional domains. Thus, these are good candidates for further experimental evaluation. Among the accessory proteins, ORF6 and ORF8 were highlighted because of their strong and weak correlation with Spike protein mutations, respectively. [ABSTRACT FROM AUTHOR]

The Toll‐like receptor (TLR)7‐ and TLR9‐dependent signalling cascade is responsible for production of a large amount of alpha interferon by plasmacytoid dendritic cells upon viral infection. Here, we show that Middle East respiratory syndrome coronavirus (MERS‐CoV) accessory protein ORF4b has the most potential among the MERS‐CoV accessory proteins to inhibit the TLR7/9‐signaling‐dependent alpha interferon production. ORF4b protein, which has a bipartite nuclear localization signal, was found to bind to IKKα, a kinase responsible for phosphorylation of interferon regulatory factor (IRF)7. This interaction caused relocation of a large proportion of IKKα from the cytoplasm to the nucleus. Studies using ORF4b and IKKα mutants demonstrated that ORF4b protein inhibited IKKα‐mediated IRF7 phosphorylation by sequestering IKKα in the nucleus and by impeding the phosphorylation process of cytoplasmic IKKα. [ABSTRACT FROM AUTHOR]

Coronaviruses (CoVs) have complex genomes that encode a fixed array of structural and nonstructural components, as well as a variety of accessory proteins that differ even among closely related viruses. Accessory proteins often play a role in the suppression of immune responses and may represent virulence factors. Despite their relevance for CoV phenotypic variability, information on accessory proteins is fragmentary. We applied a systematic approach based on homology detection to create a comprehensive catalogue of accessory proteins encoded by CoVs. Our analyses grouped accessory proteins into 379 orthogroups and 12 super‐groups. No orthogroup was shared by the four CoV genera and very few were present in all or most viruses in the same genus, reflecting the dynamic evolution of CoV genomes. We observed differences in the distribution of accessory proteins in CoV genera. Alphacoronaviruses harboured the largest diversity of accessory open reading frames (ORFs), deltacoronaviruses the smallest. However, the average number of accessory proteins per genome was highest in betacoronaviruses. Analysis of the evolutionary history of some orthogroups indicated that the different CoV genera adopted similar evolutionary strategies. Thus, alphacoronaviruses and betacoronaviruses acquired phosphodiesterases and spike‐like accessory proteins independently, whereas horizontal gene transfer from reoviruses endowed betacoronaviruses and deltacoronaviruses with fusion‐associated small transmembrane (FAST) proteins. Finally, analysis of accessory ORFs in annotated CoV genomes indicated ambiguity in their naming. This complicates cross‐communication among researchers and hinders automated searches of large data sets (e.g., PubMed, GenBank). We suggest that orthogroup membership is used together with a naming system to provide information on protein function. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are members of a superfamily of structurally related peptide hormones that includes glucagon, glucagon-like peptides, secretin, gastric inhibitory peptide (GIP) and growth hormone-releasing hormone (GHRH). VIP and PACAP exert their actions through three GPCRs - PAC1, VPAC1 and VPAC2- belonging to class B (also referred to as class II, or secretin receptor-like GPCRs). This family comprises receptors for all peptides structurally related to VIP and PACAP, and also receptors for parathyroid hormone, corticotropin-releasing factor, calcitonin and related peptides. PAC1 receptors are selective for PACAP, whereas VPAC1 and VPAC2 respond to both VIP and PACAP with high affinity. VIP and PACAP play diverse and important roles in the CNS, with functions in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury. Recent genetic studies also implicate the VPAC2 receptor in susceptibility to schizophrenia and the PAC1 receptor in post-traumatic stress disorder. In the periphery, VIP and PACAP play important roles in the control of immunity and inflammation, the control of pancreatic insulin secretion, the release of catecholamines from the adrenal medulla and as co-transmitters in autonomic and sensory neurons. This article, written by members of the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) subcommittee on receptors for VIP and PACAP, confirms the existing nomenclature for these receptors and reviews our current understanding of their structure, pharmacology and functions and their likely physiological roles in health and disease. More detailed information has been incorporated into newly revised pages in the IUPHAR database (). LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein-Coupled Receptors. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

The vasoactive intestinal peptide (VIP) is a neuropeptide with wide distribution in both central and peripheral nervous systems, where it plays important regulatory role in many physiological processes. VIP displays a large biological functions including regulation of exocrine secretions, hormone release, fetal development, immune responses, etc. VIP appears to exert beneficial effect in neuro-degenerative and inflammatory diseases. The mechanism of action of VIP implicates two subtypes of receptors (VPAC1 and VPAC2), which are members of class B receptors belonging to the super-family of GPCR. This article reviews the current knowledge regarding the structure and molecular pharmacology of VPAC receptors. The structure-function relationship of VPAC1 receptor has been extensively studied, allowing to understand the molecular basis for receptor affinity, specificity, desensitization and coupling to adenylyl cyclase. Those studies have clearly demonstrated the crucial role of the N-terminal ectodomain (N-ted) of VPAC1 receptor in VIP recognition. By using different approaches including directed mutagenesis, photoaffinity labelling, NMR, molecular modelling and molecular dynamic simulation, it has been shown that the VIP molecule interacts with the N-ted of VPAC1 receptor, which is itself structured as a 'Sushi' domain. VPAC1 receptor also interacts with a few accessory proteins that play a role in cell signalling of receptors. Recent advances in the structural characterization of VPAC receptor and more generally of class B GPCRs will lead to the design of new molecules, which could have considerable interest for the treatment of inflammatory and neuro-degenerative diseases. LINKED ARTICLES This article is part of a themed section on Secretin Family (Class B) G Protein-Coupled Receptors. To view the other articles in this section visit [ABSTRACT FROM AUTHOR]

The intracellular mechanisms underlying renal tubular epithelial cell proliferation and tubular repair following ischemia-reperfusion injury (IRI) remain poorly understood. In this report, we demonstrate that activator of G-protein signaling 3 (AGS3), an unconventional receptor-independent regulator of heterotrimeric G-protein function, influences renal tubular regeneration following IRI. In rat kidneys exposed to IRI, there was a temporal induction in renal AGS3 protein expression that peaked 72 h after reperfusion and corresponded to the repair and recovery phase following ischemic injury. Renal AGS3 expression was localized predominantly to the recovering outer medullary proximal tubular cells and was highly coexpressed with Ki-67, a marker of cell proliferation. Kidneys from mice deficient in the expression of AGS3 exhibited impaired renal tubular recovery 7 d following IRI compared to wild-type AGS3-expressing mice. Mechanistically, genetic knockdown of endogenous AGS3 mRNA and protein in renal tubular epithelial cells reduced cell proliferation in vitro. Similar reductions in renal tubular epithelial cell proliferation were observed following incubation with gallein, a selective inhibitor of G subunit activity, and lentiviral overexpression of the carboxyl-terminus of G-protein-coupled receptor kinase 2 (GRK2ct), a scavenger of Gγ subunits. In summary, these data suggest that AGS3 acts through a novel receptor-independent mechanism to facilitate renal tubular epithelial cell proliferation and renal tubular regeneration. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome (SARS) is the first emerging infectious disease of the 21st century that has been highly transmissible and fatal and was caused by a previously unknown coronavirus (SARS-CoV). The SARS epidemic in 2003 resulted in more than 8400 SARS cases and approximately 800 deaths. Existing in non-identified animal reservoirs, SARS-CoV continues to represent a threat to humans although more than four years have passed since a large outbreak of SARS, and no new cases have been reported. However, we cannot exclude the possibility of reemergence of SARS. It is hence necessary to understand the biology of the SARS-CoV to deal adequately with the next outbreak, whenever it happens. The SARS-CoV is a novel coronavirus with a large (∼30 thousand nucleotides) positive-sense, single-stranded RNA containing 14 functional open reading frames (ORFs) of which 2 large ORFs constitute the replicase gene which encodes proteins required for viral RNA syntheses. The remaining 12 ORFs encode the 4 structural proteins: spike, membrane, nucleocapsid and envelope; and eight accessory proteins. The viral genome and its expression within the host cell undergoes extensive translational and enzymatic processing to form the 4 structural, 8 accessory and 16 nonstructural proteins. In an effort to understand the molecular mechanisms or capsid assembly and viral pathogenesis, laboratories around the world have adopted a variety of approaches to answering these trivial questions. It has been our effort to consolidate all information known to date about the molecular mechanisms of the SARS-CoV into this chapter to update our readership on the current status of research. [ABSTRACT FROM AUTHOR]