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HIV-1 Tat Mediates Degradation of RON Receptor Tyrosine Kinase, a Regulator of Inflammation¹

Parisa Kalantari^2,*, Omid F. Harandi^2,, Pamela A. Hankey^2,* and Andrew J. Henderson^2,3,*,

^* Graduate Program in Pathobiology, Center for Molecular Immunology and Infectious Diseases, and Genetics Program of the Huck Institute for the Life Sciences, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, PA 16802; and Center for HIV/AIDS Care and Research, Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, Boston, MA 02118

HIV encodes several proteins, including Tat, that have been demonstrated to modulate the expression of receptors critical for innate immunity, including MHC class I, mannose receptor, and β₂-microglobulin. We demonstrate that Tat targets the receptor tyrosine kinase recepteur d’origine nantais (RON), which negatively regulates inflammation and HIV transcription, for proteosome degradation. Tat decreases cell surface RON expression in HIV-infected monocytic cells, and Tat-mediated degradation of RON protein is blocked by inhibitors of proteosome activity. Tat specifically induced down-regulation of RON and not other cell surface receptors, such as the transferrin receptor, the receptor tyrosine kinase TrkA, or monocytic markers CD14 and ICAM-1. The Tat trans activation domain is required for RON degradation, and this down-regulation is dependent on the integrity of the kinase domain of RON receptor. We propose that Tat mediates degradation of RON through a ubiquitin-proteosome pathway, and suggest that by targeting signals that modulate inflammation, Tat creates a microenvironment that is optimal for HIV replication and progression of AIDS-associated diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by funds from the Penn State Tobacco Formula Funds and National Institutes of Health Grant AI46261 (to A.J.H.), and American Heart Association Predoctoral Fellowship Grant 0415425U (to P.K.).

² Author contributions: P.K. designed research, performed experiments, analyzed data, and wrote paper; O.F.H. designed and performed experiments; P.A.H. provided key reagents and critical discussion; and A.J.H. supervised project, designed experiments, analyzed data, and wrote paper.

³ Address correspondence and reprint requests to Dr. Andrew J. Henderson, Center for HIV/AIDS Care and Research, Department of Medicine, Section of Infectious Diseases, Boston University School of Medicine, 650 Albany Street, EBRC 648, Boston, MA 02118. E-mail address: andrew.henderson{at}bmc.org or hender{at}bu.edu

⁴ Abbreviations used in this paper: TAR, trans activation response element; LTR, long terminal repeat; RON, recepteur d’origine nantais; CAT, chloramphenicol acetyltransferase.