Over the recent years, several homologues with varying degrees of genetic relatedness to hepatitis C virus (HCV) have been identified in a wide range of mammalian species. HCV infectious life cycle relies on a first critical proteolytic event of its single polyprotein, which is carried out by nonstructural protein 2 (NS2) and allows replicase assembly and genome replication. In this study, we characterized and evaluated the conservation of the proteolytic mode of action and regulatory mechanisms of NS2 across HCV and animal hepaciviruses. We first demonstrated that NS2 from equine, bat, rodent, New and Old World primate hepaciviruses also are cysteine proteases. Using tagged viral protein precursors and catalytic triad mutants, NS2 of equine NPHV and simian GBV-B, which are the most closely and distantly related viruses to HCV, respectively, were shown to function, like HCV NS2 as dimeric proteases with two composite active sites. Consistent with the reported essential role for NS3 N-terminal domain (NS3N) as HCV NS2 protease cofactor via NS3N key hydrophobic surface patch, we showed by gain/loss of function mutagenesis studies that some heterologous hepacivirus NS3N may act as cofactors for HCV NS2 provided that HCV-like hydrophobic residues are conserved. Unprecedently, however, we also observed efficient intrinsic proteolytic activity of NS2 protease in the absence of NS3 moiety in the context of C-terminal tag fusions via flexible linkers both in transiently transfected cells for all hepaciviruses studied and in the context of HCV dicistronic full-length genomes. These findings suggest that NS3N acts as a regulatory rather than essential cofactor for hepacivirus NS2 protease. Overall, unique features of NS2 including enzymatic function as dimers with two composite active sites and additional NS3-independent proteolytic activity are conserved across hepaciviruses regardless of their genetic distances, highlighting their functional significance in hepacivirus life cycle.
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http://dx.doi.org/10.1371/journal.ppat.1006863 | DOI Listing |
Int J Environ Health Res
December 2024
Laboratory of Natural Resources and Management of Sensitive Environments, University of Oum El Bouaghi, Oum El Bouaghi, Algeria.
This study investigated the chemical composition and biological activities of essential oils extracted from Daucus biseriatus collected from the Algerian Sahara. Gas chromatography-mass spectrometry identified 57 compounds, constituting 97.09% of the oils, with myristicin (23.
View Article and Find Full Text PDFEur J Med Res
December 2024
Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong, China.
The gut microbiota is a complex and dynamic ecosystem that plays a crucial role in human health and disease, including obesity, diabetes, cardiovascular diseases, neurodegenerative diseases, inflammatory bowel disease, and cancer. Chronic inflammation is a common feature of these diseases and is closely related to angiogenesis (the process of forming new blood vessels), which is often dysregulated in pathological conditions. Inflammation potentially acts as a central mediator.
View Article and Find Full Text PDFAnim Microbiome
December 2024
School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background: Dogs-whether pets, rural, or stray-exhibit distinct living styles that influence their fecal microbiota and resistomes, yet these dynamics remain underexplored. This study aimed to analyze and compare the fecal microbiota and resistomes of three groups of dogs (37 pets, 20 rural, and 25 stray dogs) in Shanghai, China.
Results: Metagenomic analysis revealed substantial differences in fecal microbial composition and metabolic activities among the dog groups.
BMC Plant Biol
December 2024
School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
Nitrogen (N) is one of the three major elements required for plant growth and development. It is of great significance to study the effects of different nitrogen application levels on the growth and root exudates of Phlomoides rotata, and can provide a theoretical basis for its scientific application of fertilizer to increase production. In this study, Phlomoides rotata were grown under different nitrogen conditions for two months.
View Article and Find Full Text PDFGut Microbes
December 2025
Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
Maternal gut microbiota composition contributes to the status of the neonatal immune system and could influence the early life higher susceptibility to viral respiratory infections. Using a novel protocol of murine maternal probiotic supplementation, we report that perinatal exposure to () or () increases the influenza A/PR8 virus (IAV) clearance in neonates. Following either supplementation, type 1 conventional dendritic cells (cDC1) were amplified in the lymph nodes leading to an enhanced IAV antigen-experienced IFN-γ producing effector CD8 T cells in neonates and IAV-specific resident memory CD8 T cells in adulthood.
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