HIV-1 Tat mediates degradation of RON receptor tyrosine kinase, a regulator of inflammation.
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.
Kalantari
Parisa
P
Graduate Program in Pathobiology, Center for Molecular Immunology and Infectious Diseases, Pennsylvania State University, PA 16802, USA.
Harandi
Omid F
OF
Hankey
Pamela A
PA
Henderson
Andrew J
AJ
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*
D025801:Ubiquitin; D054322:tat Gene Products, Human Immunodeficiency Virus; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D046988:Proteasome Endopeptidase Complex