title: Endolysosomal trafficking of viral G protein-coupled receptor functions in innate immunity and control of viral oncogenesis.
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.
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Dong
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Adam
authors.initials: A
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Yih-Sheng
authors.initials: YS
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Rhea M
authors.initials: RM
authors.lastname: Sumpter
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY 10032;
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.affiliation: Department of Internal Medicine, Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, TX 75390; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX 75390 beth.levine@utsouthwestern.edu.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D001343:Autophagy / Q000502:physiology; D000071186:Beclin-1; D002472:Cell Transformation, Viral; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D006579:Heterozygote; D006801:Humans; D007113:Immunity, Innate; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008247:Lysosomes / Q000502:physiology* / Q000821:virology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D011506:Proteins / Q000502:physiology; D059748:Proteolysis; D034741:RNA, Small Interfering; D019707:Receptors, Chemokine / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000473:pathology / Q000821:virology; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C105181:ORF74 protein, Human herpesvirus 8; D011506:Proteins; D034741:RNA, Small Interfering; D019707:Receptors, Chemokine; D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins; C424444:WFIKKN2 protein, human
keywords: Beclin 2; autophagy; endolysosomal trafficking; oncogenesis; viral GPCR