title: Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II.
abstract: Bone morphogenetic proteins (BMPs) are critically involved in early development and cell differentiation. In humans, dysfunction of the bone morphogenetic protein type II receptor (BMPR-II) is associated with pulmonary arterial hypertension (PAH) and neoplasia. The ability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma and primary effusion lymphoma, to down-regulate cell surface receptor expression is well documented. Here we show that KSHV infection reduces cell surface BMPR-II. We propose that this occurs through the expression of the viral lytic gene, K5, a ubiquitin E3 ligase. Ectopic expression of K5 leads to BMPR-II ubiquitination and lysosomal degradation with a consequent decrease in BMP signaling. The down-regulation by K5 is dependent on both its RING domain and a membrane-proximal lysine in the cytoplasmic domain of BMPR-II. We demonstrate that expression of BMPR-II protein is constitutively regulated by lysosomal degradation in vascular cells and provide preliminary evidence for the involvement of the mammalian E3 ligase, Itch, in the constitutive degradation of BMPR-II. Disruption of BMP signaling may therefore play a role in the pathobiology of diseases caused by KSHV infection, as well as KSHV-associated tumorigenesis and vascular disease.
authors.affiliation: From theDepartment of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge, Cambridgeshire CB2 0QQ, United Kingdom.
authors.forename: Hannah J
authors.initials: HJ
authors.lastname: Durrington
authors.forename: Paul D
authors.initials: PD
authors.lastname: Upton
authors.forename: Simon
authors.initials: S
authors.lastname: Hoer
authors.forename: Jessica
authors.initials: J
authors.lastname: Boname
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dunmore
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Trina K
authors.initials: TK
authors.lastname: Crilley
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Butler
authors.forename: David J
authors.initials: DJ
authors.lastname: Blackbourn
authors.forename: Gerard B
authors.initials: GB
authors.lastname: Nash
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Lehner
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D052006:Bone Morphogenetic Protein Receptors, Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D006367:HeLa Cells; D019288:Herpesvirus 8, Human / Q000201:enzymology / Q000235:genetics / Q000502:physiology; D006801:Humans; D008247:Lysosomes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; D014764:Viral Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D052006:Bone Morphogenetic Protein Receptors, Type II