Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II.
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.
Durrington
Hannah J
HJ
From theDepartment of Medicine, University of Cambridge School of Clinical Medicine, Box 157, Addenbrooke's Hospital, Hills Road, Cambridge, Cambridgeshire CB2 0QQ, United Kingdom.
Upton
Paul D
PD
Hoer
Simon
S
Boname
Jessica
J
Dunmore
Benjamin J
BJ
Yang
Jun
J
Crilley
Trina K
TK
Butler
Lynn M
LM
Blackbourn
David J
DJ
Nash
Gerard B
GB
Lehner
Paul J
PJ
Morrell
Nicholas W
NW
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
D012097:Repressor Proteins; D014764:Viral Proteins; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases; D052006:Bone Morphogenetic Protein Receptors, Type II