title: The basic domain of HIV-tat transactivating protein is essential for its targeting to lipid rafts and regulating fibroblast growth factor-2 signaling in podocytes isolated from children with HIV-1-associated nephropathy.
abstract: Podocyte injury has a critical role in the pathogenesis of HIV-associated nephropathy (HIVAN). The HIV-1 transactivator of transcription (Tat), combined with fibroblast growth factor-2 (FGF-2), can induce the dedifferentiation and proliferation of cultured human podocytes. Cellular internalization of Tat requires interactions with heparan sulfate proteoglycans and cholesterol-enriched lipid rafts (LRs). However, the specific distribution of Tat in human podocytes and its ability to associate with LRs have not been documented. Here, we found that Tat is preferentially recruited to LRs in podocytes isolated from children with HIVAN. Furthermore, we identified arginines in the basic domain (RKKRRQRRR) of Tat as essential for (1) targeting Tat to LRs, (2) Tat-mediated increases in the expression of Rho-A and matrix metalloproteinase-9 in LRs, and (3) Tat-mediated enhancement of FGF-2 signaling in human podocytes and HIV-transgenic mouse kidneys and the exacerbation of renal lesions in these mice. Tat carrying alanine substitutions in the basic domain (AKKAAQAAA) remained localized in the cytosol and did not associate with LRs or enhance FGF-2 signaling in cultured podocytes. These results show the specific association of Tat with LRs in podocytes isolated from children with HIVAN, confirm Tat as a regulator of FGF-2 signaling in LRs, and identify the key domain of Tat responsible for promoting these effects and aggravating renal injury in HIV-transgenic mice. Moreover, these results provide a molecular framework for developing novel therapies to improve the clinical outcome of children with HIVAN.
authors.affiliation: Center for Genetic Medicine Research and.
authors.forename: Xuefang
authors.initials: X
authors.lastname: Xie
authors.affiliation: Center for Genetic Medicine Research and Department of Pediatrics, George Washington University, Washington, DC; and.
authors.forename: Anamaris M
authors.initials: AM
authors.lastname: Colberg-Poley
authors.affiliation: Center for Genetic Medicine Research and.
authors.forename: Jharna R
authors.initials: JR
authors.lastname: Das
authors.affiliation: Center for Genetic Medicine Research and.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Genetic Medicine Research and.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Center for Genetic Medicine Research and Department of Pediatrics, George Washington University, Washington, DC; and.
authors.forename: Pingtao
authors.initials: P
authors.lastname: Tang
authors.affiliation: Center for Genetic Medicine Research and Department of Pediatrics, George Washington University, Washington, DC; and.
authors.forename: Marina
authors.initials: M
authors.lastname: Jerebtsova
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Center for Genetic Medicine Research and Department of Pediatrics, George Washington University, Washington, DC; and Division of Nephrology, Children's National Medical Center, Washington, DC; Pray@childrensnational.org.
authors.forename: Patricio E
authors.initials: PE
authors.lastname: Ray
mesh_terms: D016263:AIDS-Associated Nephropathy / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001120:Arginine / Q000378:metabolism; D018929:Cell Culture Techniques; D002648:Child; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015497:HIV-1; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D021962:Membrane Microdomains / Q000502:physiology*; D008822:Mice, Transgenic; D050199:Podocytes / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000502:physiology*
chemical_list: D054322:tat Gene Products, Human Immunodeficiency Virus; D016222:Fibroblast Growth Factor 2; D001120:Arginine; D020780:Matrix Metalloproteinase 9; D020742:rhoA GTP-Binding Protein
keywords: Cell Signaling; HIV nephropathy; cytokines; pediatric nephrology; podocyte; proteinuria