title: HIV-1 Tat mediates degradation of RON receptor tyrosine kinase, a regulator of inflammation.
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.
authors.affiliation: Graduate Program in Pathobiology, Center for Molecular Immunology and Infectious Diseases, Pennsylvania State University, PA 16802, USA.
authors.forename: Parisa
authors.initials: P
authors.lastname: Kalantari
authors.forename: Omid F
authors.initials: OF
authors.lastname: Harandi
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Hankey
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Henderson
mesh_terms: D002460:Cell Line; D005822:Genetic Vectors; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007249:Inflammation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection; D020298:U937 Cells; D025801:Ubiquitin / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D054322:tat Gene Products, Human Immunodeficiency Virus; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D046988:Proteasome Endopeptidase Complex