Representing a basal branch of arachnids, scorpions are known as ‘living
fossils’ that maintain an ancient anatomy and are adapted to have survived
extreme climate changes. Here we report the genome sequence of Mesobuthus
martensii, containing 32,016 protein-coding genes, the most among sequenced
arthropods. Although M. martensii appears to evolve conservatively, it has a
greater gene family turnover than the insects that have undergone diverse morphological
and physiological changes, suggesting the decoupling of the molecular and morphological
evolution in scorpions. Underlying the long-term adaptation of scorpions is the
expansion of the gene families enriched in basic metabolic pathways, signalling
pathways, neurotoxins and cytochrome P450, and the different dynamics of expansion
between the shared and the scorpion lineage-specific gene families. Genomic and
transcriptomic analyses further illustrate the important genetic features associated
with prey, nocturnal behaviour, feeding and detoxification. The M. martensii
genome reveals a unique adaptation model of arthropods, offering new insights into the
genetic bases of the living fossils.
Rationale:
Many viral infections are known to activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. However, the role of p38 activation in viral infection and the underlying mechanism remain unclear. The role of virus-hijacked p38 MAPK activation in viral infection was investigated in this study.
Methods:
The correlation of hepatitis C virus (HCV) infection and p38 activation was studied in patient tissues and primary human hepatocytes (PHHs) by immunohistochemistry and western blotting. Coimmunoprecipitation, GST pulldown and confocal microscopy were used to investigate the interaction of p38α and the HCV core protein.
In vitro
kinase assays and mass spectrometry were used to analyze the phosphorylation of the HCV core protein. Plaque assays, quantitative real time PCR (qRT-PCR), western blotting, siRNA and CRISPR/Cas9 were used to determine the effect of p38 activation on viral replication.
Results:
HCV infection was associated with p38 activation in clinical samples. HCV infection increased p38 phosphorylation by triggering the interaction of p38α and TGF-β activated kinase 1 (MAP3K7) binding protein 1 (TAB1). TAB1-mediated p38α activation facilitated HCV replication, and pharmaceutical inhibition of p38α activation by SB203580 suppressed HCV infection at the viral assembly step. Activated p38α interacted with the N-terminal region of the HCV core protein and subsequently phosphorylated the HCV core protein, which promoted HCV core protein oligomerization, an essential step for viral assembly. As expected, SB203580 or the HCV core protein N-terminal peptide (CN-peptide) disrupted the p38α-HCV core protein interaction, efficiently impaired HCV assembly and impeded normal HCV replication in both cultured cells and primary human hepatocytes. Similarly, severe fever with thrombocytopenia syndrome virus (SFTSV), herpes simplex virus type 1 (HSV-1) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection also activated p38 MAPK. Most importantly, pharmacological blockage of p38 activation by SB203580 effectively inhibited SFTSV, HSV-1 and SARS-CoV-2.
Conclusion:
Our study shows that virus-hijacked p38 activation is a key event for viral replication and that pharmacological blockage of p38 activation is an antiviral strategy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.