c-Cbl-Mediated Selective Virus-Receptor Translocations into Lipid Rafts Regulate Productive Kaposi's Sarcoma-Associated Herpesvirus Infection in Endothelial Cells
- 1 December 2011
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 85 (23), 12410-12430
- https://doi.org/10.1128/jvi.05953-11
Abstract
During target cell entry and infection, many enveloped and nonenveloped viruses utilize cell surface receptors that translocate into lipid rafts (LRs). However, the mechanism behind this translocation is not known. Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with the human microvascular dermal endothelial (HMVEC-d) cell surface heparan sulfate (HS), integrins α3β1, αVβ3, and αVβ5, and the amino acid transporter x-CT protein and enters via c-Cbl-bleb-mediated macropinocytosis (Veettil et al., J. Virol. 82: 12126-12144, 2008; Veettil et al., PLoS Pathog. 6: e1001238, 2010). Here we have demonstrated that very early during infection (1 min postinfection), c-Cbl induced the selective translocation of KSHV into the LR along with the α3β1, αVβ3, and x-CT receptors but not αVβ5. Activated c-Cbl localized with LRs at the junctional base of macropinocytic blebs. LR-translocated α3β1 and αVβ3 were monoubiquitinated, leading to productive macropinocytic entry, whereas non-LR-associated αVβ5 was polyubiquitinated, leading to clathrin entry that was targeted to lysosomes. c-Cbl knockdown blocked the macropinocytosis and receptor translocation and diverted KSHV to a clathrin-lysosomal noninfectious pathway. Similar results were also seen by LR disruption with MβCD. These studies provide the first evidence that c-Cbl regulates selective KSHV-α3β1, -αVβ3, and -x-CT receptor translocations into the LRs and differential ubiquitination of receptors which are critical determinants of the macropinocytic entry route and productive infection of KSHV. Our studies suggest that interventions targeting c-Cbl and LRs are potential avenues to block KSHV infection of endothelial cells.This publication has 52 references indexed in Scilit:
- Lipid Rafts of Primary Endothelial Cells Are Essential for Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8-Induced Phosphatidylinositol 3-Kinase and RhoA-GTPases Critical for Microtubule Dynamics and Nuclear Delivery of Viral DNA but Dispensable for Binding and EntryJournal of Virology, 2007
- Transport of protein toxins into cells: pathways used by ricin, cholera toxin and Shiga toxinFEBS Letters, 2002
- Human Immunodeficiency Virus Type 1 Uses Lipid Raft-Colocalized CD4 and Chemokine Receptors for Productive Entry into CD4 + T CellsJournal of Virology, 2002
- Integrin α3β1 (CD 49c/29) Is a Cellular Receptor for Kaposi's Sarcoma-Associated Herpesvirus (KSHV/HHV-8) Entry into the Target CellsCell, 2002
- Cell Surface Heparan Sulfate Is a Receptor for Human Herpesvirus 8 and Interacts with Envelope Glycoprotein K8.1Journal of Virology, 2001
- Human Herpesvirus 8 Envelope Glycoprotein K8.1A Interaction with the Target Cells Involves Heparan SulfateJournal of Virology, 2001
- Human Herpesvirus 8 Envelope-Associated Glycoprotein B Interacts with Heparan Sulfate-like MoietiesVirology, 2001
- Rapid Cycling of Lipid Raft Markers between the Cell Surface and Golgi ComplexThe Journal of cell biology, 2001
- Cbl: many adaptations to regulate protein tyrosine kinasesNature Reviews Molecular Cell Biology, 2001
- Lipid rafts and signal transductionNature Reviews Molecular Cell Biology, 2000