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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / physiology*
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Autophagy / physiology
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Beclin-1
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Cell Transformation, Viral
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Crosses, Genetic
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Disease Models, Animal
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Endocytosis / physiology
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Genetic Predisposition to Disease
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HEK293 Cells
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Herpesvirus 8, Human / immunology
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Herpesvirus 8, Human / pathogenicity
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Herpesvirus 8, Human / physiology*
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Heterozygote
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Humans
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Immunity, Innate
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Intercellular Signaling Peptides and Proteins
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Interleukin-6 / biosynthesis
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Interleukin-6 / genetics
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Lysosomes / physiology*
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Lysosomes / virology
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Mice
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NF-kappa B / metabolism
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Proteins / physiology
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Proteolysis
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RNA, Small Interfering
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Receptors, Chemokine / metabolism
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Receptors, G-Protein-Coupled / metabolism*
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Sarcoma, Kaposi / genetics
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Sarcoma, Kaposi / pathology
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Sarcoma, Kaposi / virology
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Skin Neoplasms / virology
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Viral Proteins / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Beclin-1
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Becn1 protein, mouse
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IL6 protein, human
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Intercellular Signaling Peptides and Proteins
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Interleukin-6
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NF-kappa B
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ORF74 protein, Human herpesvirus 8
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Proteins
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RNA, Small Interfering
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Receptors, Chemokine
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Receptors, G-Protein-Coupled
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Viral Proteins
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WFIKKN2 protein, human