Human cytomegalovirus downregulates expression of receptors for platelet-derived growth factor by smooth muscle cells.
Infection by human cytomegalovirus (HCMV) is associated with the development of vascular diseases and may cause severe brain damage in infected fetuses. Platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and -beta) control important cellular processes associated with atherosclerosis and fetal development. In the present investigation, our goal was to determine whether infection by HCMV can influence the expression of PDGFR-alpha and -beta in human smooth muscle cells (SMCs). In connection with HCMV infection in vitro the levels of PDGFR-alpha and -beta at the cell surface and in the total cellular protein of SMCs were reduced in parallel with decreases in the levels of the corresponding mRNAs. These effects were dependent on immediate-early (IE) or early (E) HCMV gene products, since inhibition of late genes did not prevent HCMV from affecting the expression of PDGFR-alpha and -beta. The downregulation of PDGFR caused by HCMV was dose dependent. Furthermore, confocal microscopy revealed that the localization of PDGFR-beta was altered in HCMV-infected cells, in which this protein colocalized with proteins associated with endosomes (Rab4 and -5) and lysosomes (Lamp1 and -2), indicating entrance into pathways for protein degradation. Altogether these observations indicate that an IE and/or E HCMV protein(s) downregulates the expression of PDGFR-alpha and -beta in SMCs. This phenomenon may disrupt cellular processes of importance in connection with cellular differentiation, migration, and/or proliferation. These observations may explain why congenital infection with HCMV can cause fetal brain damage.
Gredmark
Sara
S
Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Strååt
Klas
K
Homman-Loudiyi
Mohammed
M
Kannisto
Katja
K
Söderberg-Nauclér
Cecilia
C
D000956:Antigens, Viral / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000502:physiology; D008247:Lysosomes / Q000378:metabolism; D018613:Microscopy, Confocal; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000821:virology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis*; D020695:rab4 GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
D000956:Antigens, Viral; D017874:Immediate-Early Proteins; D012333:RNA, Messenger; C044582:immediate-early proteins, cytomegalovirus; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta; D020695:rab4 GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins