The Ubiquitin/Proteasome System Mediates Entry and Endosomal Trafficking of Kaposi's Sarcoma-Associated Herpesvirus in Endothelial Cells

PLoS Pathogens

Fengchun Ye¹  Meilan He²  Colleen Witt²  Wei Zhang³  Whitney Greene³  Shou-Jiang Gao³ 

[1] Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, Texas, United States of America;Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America;Tumor Virology Program, Greehey Children's Cancer Research Institute, and Department of Pediatrics, University of Texas Health Science Center San Antonio, San Antonio, Texas, United States of America

关键词: Virions;    Integrins;    Proteasomes;    Ubiquitination;    Kaposi's sarcoma-associated herpesvirus;    Cell membranes;    Ligases;    Endothelial cells;   

DOI  :  10.1371/journal.ppat.1002703

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Ubiquitination, a post-translational modification, mediates diverse cellular functions including endocytic transport of molecules. Kaposi's sarcoma-associated herpesvirus (KSHV), an enveloped herpesvirus, enters endothelial cells primarily through clathrin-mediated endocytosis. Whether ubiquitination and proteasome activity regulates KSHV entry and endocytosis remains unknown. We showed that inhibition of proteasome activity reduced KSHV entry into endothelial cells and intracellular trafficking to nuclei, thus preventing KSHV infection of the cells. Three-dimensional (3-D) analyses revealed accumulation of KSHV particles in a cytoplasmic compartment identified as EEA1+ endosomal vesicles upon proteasome inhibition. KSHV particles are colocalized with ubiquitin-binding proteins epsin and eps15. Furthermore, ubiquitination mediates internalization of both KSHV and one of its receptors integrin β1. KSHV particles are colocalized with activated forms of the E3 ligase c-Cbl. Knock-down of c-Cbl or inhibition of its phosphorylation reduced viral entry and intracellular trafficking, resulting in decreased KSHV infectivity. These results demonstrate that ubiquitination mediates internalization of both KSHV and one of its cognate receptors integrin β1, and identify c-Cbl as a potential E3 ligase that facilitates this process.

【 授权许可】

CC BY