Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis

Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):2994-9. doi: 10.1073/pnas.1601860113. Epub 2016 Feb 29.

Abstract

The ubiquitin-proteasome system degrades viral oncoproteins and other microbial virulence factors; however, the role of endolysosomal degradation pathways in these processes is unclear. Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma, and a constitutively active viral G protein-coupled receptor (vGPCR) contributes to the pathogenesis of KSHV-induced tumors. We report that a recently discovered autophagy-related protein, Beclin 2, interacts with KSHV GPCR, facilitates its endolysosomal degradation, and inhibits vGPCR-driven oncogenic signaling. Furthermore, monoallelic loss of Becn2 in mice accelerates the progression of vGPCR-induced lesions that resemble human Kaposi's sarcoma. Taken together, these findings indicate that Beclin 2 is a host antiviral molecule that protects against the pathogenic effects of KSHV GPCR by facilitating its endolysosomal degradation. More broadly, our data suggest a role for host endolysosomal trafficking pathways in regulating viral pathogenesis and oncogenic signaling.

Keywords: Beclin 2; autophagy; endolysosomal trafficking; oncogenesis; viral GPCR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Autophagy / physiology
  • Beclin-1
  • Cell Transformation, Viral
  • Crosses, Genetic
  • Disease Models, Animal
  • Endocytosis / physiology
  • Genetic Predisposition to Disease
  • HEK293 Cells
  • Herpesvirus 8, Human / immunology
  • Herpesvirus 8, Human / pathogenicity
  • Herpesvirus 8, Human / physiology*
  • Heterozygote
  • Humans
  • Immunity, Innate
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Lysosomes / physiology*
  • Lysosomes / virology
  • Mice
  • NF-kappa B / metabolism
  • Proteins / physiology
  • Proteolysis
  • RNA, Small Interfering
  • Receptors, Chemokine / metabolism
  • Receptors, G-Protein-Coupled / metabolism*
  • Sarcoma, Kaposi / genetics
  • Sarcoma, Kaposi / pathology
  • Sarcoma, Kaposi / virology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • Skin Neoplasms / virology
  • Viral Proteins / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • IL6 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-6
  • NF-kappa B
  • ORF74 protein, Human herpesvirus 8
  • Proteins
  • RNA, Small Interfering
  • Receptors, Chemokine
  • Receptors, G-Protein-Coupled
  • Viral Proteins
  • WFIKKN2 protein, human