title: HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders.
abstract: Antiretroviral therapy has increased the life span of HIV+ individuals; however, HIV-associated neurocognitive disorder (HAND) occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain β II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND.
authors: Departments of Pathology and.
authors: Jerel
authors: J
authors: Fields
authors: Departments of Pathology and.
authors: Wilmar
authors: W
authors: Dumaop
authors: Simona
authors: S
authors: Eleuteri
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Simona
authors: S
authors: Elueteri
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Sofia
authors: http://orcid.org/0000-0001-5241-3905
authors: S
authors: Campos
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Elisabeth
authors: E
authors: Serger
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Margarita
authors: M
authors: Trejo
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Kori
authors: K
authors: Kosberg
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Anthony
authors: A
authors: Adame
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Brian
authors: B
authors: Spencer
authors: Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and.
authors: Edward
authors: E
authors: Rockenstein
authors: Departments of Cell Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas 76107.
authors: Johnny J
authors: JJ
authors: He
authors: Departments of Pathology and Neurosciences, University of California San Diego, La Jolla, California 92093-0624 and emasliah@ucsd.edu.
authors: Eliezer
authors: E
authors: Masliah
mesh_terms: D015526:AIDS Dementia Complex / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015497:HIV-1 / Q000235:genetics; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: HIV; LAMP2A; Tat; autophagy
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