title: HIV-1 Tat Inhibits Autotaxin Lysophospholipase D Activity and Modulates Oligodendrocyte Differentiation.
abstract: White matter injury has been frequently reported in HIV+patients. Previous studies showed that HIV-1 Tat (transactivator of transcription), a viral protein that is produced and secreted by HIV-infected cells, is toxic to young, immature oligodendrocytes (OLGs). Adding Tat to the culture medium reduced the viability of immature OLGs, and the surviving OLGs exhibited reduced process networks. OLGs produce and secrete autotaxin (ATX), an ecto-enzyme containing a lysophospholipase D (lysoPLD) activity that converts lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a lipid signaling molecule that stimulates OLG differentiation. We hypothesized that Tat affects OLG development by interfering with the ATX-LPA signaling pathway. Our data show that Tat treatment leads to changes in the expression of OLG differentiation genes and the area of OLG process networks, both of which can be rescued by LPA. Tat-treated OLGs showed no change in LPA receptor expression but significantly decreased extracellular ATX levels and lysoPLD activity. In Tat transgenic mice, expression of Tat in vivo leads to decreased OLG ATX secretion. Furthermore, co-immunoprecipitation experiments revealed a potential physical interaction between Tat and ATX. Together, these data strongly suggest two functional implications of Tat blocking ATX's lysoPLD activity. On one hand, it attenuates OLG differentiation, and on the other hand it interferes with the protective effects of LPA on OLG process morphology.
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Wheeler
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Babette
authors.initials: B
authors.lastname: Fuss
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA Institute for Drug and Alcohol Studies, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Knapp
authors.affiliation: Department of Anatomy and Neurobiology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA ShiPing.Zou@vcuhealth.org.
authors.forename: ShiPing
authors.initials: S
authors.lastname: Zou
keywords: Tat; autotaxin; lysophosphatidic acid; myelin; neuroAIDS; oligodendrocyte