Abstract
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 beta(2)-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.
Highlights
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We propose that Tat mediates degradation of recepteur d’origine nantais (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
To determine whether Tat has the ability to overcome the suppressive effects of RON on HIV transcription, U937RON and U937-murine stem cell virus (MSCV) were cotransfected with Tat and a HIV long terminal repeat (LTR)-luciferase reporter (LTR-Luc) and assayed for luciferase activity
Summary
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. The receptor tyrosine kinase recepteur d’origine nantais (RON), which belongs to the Met proto-oncogene family [34], is a critical regulator of macrophage function and inflammation [35]. RON is expressed mostly on tissue resident macrophages and regulates multiple cellular responses, including proliferation, differentiation, apoptosis, phagocytosis, and cell motility [35,36,37]. Activated macrophages from RON knockout mice produce elevated levels of NO in vitro and in vivo, and have demonstrated increased susceptibility to endotoxic shock as well as to autoimmune diseases mediated by inflammation [43,44,45]. RON knockout mice have compromised cell-mediated immunity, as demonstrated by an increased
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