ArticlePLoS pathogens2015
Herpesviral G protein-coupled receptors activate NFAT to induce tumor formation via inhibiting the SERCA calcium ATPase.
Article in PLoS pathogens, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 31 citations in OpenAlex.
- Article
- Human and viral chemokines differentially modulate G protein signaling, β-arrestin recruitment and chemotaxis mediated by the viral G protein-coupled receptor ORF74.Cell communication and signaling : CCS · 2025Article
- Disrupting the OTUD4-USP7 deubiquitinase complex to suppress herpesvirus replication: a novel antiviral strategy.PLoS pathogens · 2025Article
- Palmitoylation of KSHV pORF55 is required for Golgi localization and efficient progeny virion production.PLoS pathogens · 2024Article
- Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases.PLoS pathogens · 2024Article
- STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.Nature cell biology · 2023Article
- Oncolytic herpes simplex virus armed with a bacterial GBP1 degrader improves antitumor activity.Molecular therapy oncolytics · 2023Article
- Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses.mBio · 2023Article
- Engineering inducible biomolecular assemblies for genome imaging and manipulation in living cells.Nature communications · 2022Article
- DYRK1A activates NFATC1 to increase glioblastoma migration.Cancer medicine · 2021Article
- DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity.Nature communications · 2020Article
- The constitutive activity of the viral-encoded G protein-coupled receptor US28 supports a complex signalling network contributing to cancer development.Biochemical Society transactions · 2020Review
- KSHV activates unfolded protein response sensors but suppresses downstream transcriptional responses to support lytic replication.PLoS pathogens · 2019Article
- Article
- Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein Facilitates Viral Replication.Cell host & microbe · 2018Article
- CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation.PLoS pathogens · 2018Article
- US28, a Virally-Encoded GPCR as an Antiviral Target for Human Cytomegalovirus Infection.Biomolecules & therapeutics · 2017Review
- Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers.HIV/AIDS (Auckland, N.Z.) · 2017Review
- Hijacking GPCRs by viral pathogens and tumor.Biochemical pharmacology · 2016Review
- KSHV-Mediated Angiogenesis in Tumor Progression.Viruses · 2016Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
G protein-coupled receptors (GPCRs) constitute the largest family of proteins that transmit signal to regulate an array of fundamental biological processes. Viruses deploy diverse tactics to hijack and harness intracellular signaling events induced by GPCR. Herpesviruses encode multiple GPCR homologues that are implicated in viral pathogenesis. Cellular GPCRs are primarily regulated by their cognate ligands, while herpesviral GPCRs constitutively activate downstream signaling cascades, including the nuclear factor of activated T cells (NFAT) pathway. However, the roles of NFAT activation and mechanism thereof in viral GPCR tumorigenesis remain unknown. Here we report that GPCRs of human Kaposi's sarcoma-associated herpesvirus (kGPCR) and cytomegalovirus (US28) shortcut NFAT activation by inhibiting the sarcoplasmic reticulum calcium ATPase (SERCA), which is necessary for viral GPCR tumorigenesis. Biochemical approaches, entailing pharmacological inhibitors and protein purification, demonstrate that viral GPCRs target SERCA2 to increase cytosolic calcium concentration. As such, NFAT activation induced by vGPCRs was exceedingly sensitive to cyclosporine A that targets calcineurin, but resistant to inhibition upstream of ER calcium release. Gene expression profiling identified a signature of NFAT activation in endothelial cells expressing viral GPCRs. The expression of NFAT-dependent genes was up-regulated in tumors derived from tva-kGPCR mouse and human KS. Employing recombinant kGPCR-deficient KSHV, we showed that kGPCR was critical for NFAT-dependent gene expression in KSHV lytic replication. Finally, cyclosporine A treatment diminished NFAT-dependent gene expression and tumor formation induced by viral GPCRs. These findings reveal essential roles of NFAT activation in viral GPCR tumorigenesis and a mechanism of "constitutive" NFAT activation by viral GPCRs.
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