CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation

Richard Hunte, Patricia Alonso, Remy Thomas, Cassandra Alexandria Bazile, Juan Carlos Ramos, Louise van der Weyden, Juan Dominguez-Bendala, Wasif Noor Khan, Noula Shembade

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Approximately 12% of all human cancers worldwide are caused by infections with oncogenic viruses. Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) is one of the oncogenic viruses responsible for human cancers, including Kaposi’s sarcoma (KS), Primary Effusion Lymphoma (PEL), and the lymphoproliferative disorder multicentric Castleman’s disease (MCD). Chronic inflammation mediated by KSHV infection plays a decisive role in the development and survival of these cancers. NF-κB, a family of transcription factors regulating inflammation, cell survival, and proliferation, is persistently activated in KSHV-infected cells. The KSHV latent and lytic expressing oncogenes involved in NF-κB activation are vFLIP/K13 and vGPCR, respectively. However, the mechanisms by which NF-κB is activated by vFLIP and vGPCR are poorly understood. In this study, we have found that a host molecule, Cell Adhesion Molecule 1 (CADM1), is robustly upregulated in KSHV-infected PBMCs and KSHV-associated PEL cells. Further investigation determined that both vFLIP and vGPCR interacted with CADM1. The PDZ binding motif localized at the carboxyl terminus of CADM1 is essential for both vGPCR and vFLIP to maintain chronic NF-κB activation. Membrane lipid raft associated CADM1 interaction with vFLIP is critical for the initiation of IKK kinase complex and NF-κB activation in the PEL cells. In addition, CADM1 played essential roles in the survival of KSHV-associated PEL cells. These data indicate that CADM1 plays key roles in the activation of NF-κB pathways during latent and lytic phases of the KSHV life cycle and the survival of KSHV-infected cells.

Original languageEnglish
Article numbere1006968
JournalPLoS Pathogens
Volume14
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018

    Fingerprint

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Hunte, R., Alonso, P., Thomas, R., Bazile, C. A., Ramos, J. C., van der Weyden, L., Dominguez-Bendala, J., Khan, W. N., & Shembade, N. (2018). CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-κB activation. PLoS Pathogens, 14(4), [e1006968]. https://doi.org/10.1371/journal.ppat.1006968