title: Neuroprotective activity of pDING in response to HIV-1 Tat.
abstract: Although neurons are not productively infected with HIV-1, neuronal injury and death are frequently seen in the brains of AIDS patients with neurological and neurocognitive disorders. Evidently, viral proteins including Tat and cellular inflammatory factors released by activated and/or infected microglia, macrophages, and astrocytes contribute to neuronal cell death. Several studies have demonstrated that HIV-1 associated neuronal cell injury is mediated by dysregulation of signaling pathways that are controlled, in part, by a class of serine/threonine kinases. In this study, we demonstrate that pDING, a novel plant-derived phosphate binding protein has the capacity to reduce the severity of injury and death caused by HIV-1 and its neurotoxic Tat protein. We demonstrate that pDING, also called p27SJ/p38SJ, protects cells from the loss of neuronal processes induced by Tat and promotes neuronal outgrowth after Tat-mediated injury. Further, expression of pDING prevents Tat-induced oxidative stress and mitochondrial permeability. With its profound phosphatase activity, pDING controls the activity of several kinases including MAPK, Cdk5, and their downstream target protein, MEF2, which is implicated in neuronal cell protection. Our results show that expression of pDING in neuronal cells diminishes the level of hyperphosphorylated forms of Cdk5 and MEF2 caused by Tat and the other neurotoxic agents that are secreted by the HIV-1 infected cells. These observations suggest that pDING, through its phosphatase activity, has the ability to manipulate the state of phosphorylation and activity of several factors involved in neuronal cell health in response to HIV-1.
authors: Department of Neuroscience, Center for Neurovirology, Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: Nune
authors: N
authors: Darbinian
authors: Kamel
authors: K
authors: Khalili
authors: Shohreh
authors: S
authors: Amini
mesh_terms: D016923:Cell Death; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020902:Hypericum / Q000737:chemistry; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018384:Oxidative Stress / Q000187:drug effects; D028044:Phosphate-Binding Proteins / Q000378:metabolism / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D010940:Plant Proteins / Q000494:pharmacology*; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000633:toxicity*
chemical_list: D028044:Phosphate-Binding Proteins; D010940:Plant Proteins; D054322:tat Gene Products, Human Immunodeficiency Virus; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D010744:Phosphoric Monoester Hydrolases
references: Neuron. 2003 Apr 10;38(1):33-46
references: 12691662
references: Cell. 2003 Jul 25;114(2):229-39
references: 12887924
references: Neuroscience. 2005;135(3):781-90
references: 16111829
references: Neuron. 2006 Apr 6;50(1):13-8
references: 16600851
references: Neurotox Res. 2009 Oct;16(3):205-20
references: 19526283
references: Cell Death Differ. 2009 May;16(5):674-83
references: 19148185
references: Gene Ther. 2006 Feb;13(4):288-95
references: 16251997
references: Nat Rev Neurosci. 2009 Jul;10(7):481-94
references: 19543220
references: Neurotox Res. 2005 Oct;8(1-2):119-34
references: 16260390
references: J Cell Biochem. 2011 Jan;112(1):225-32
references: 21117063
references: Neuron. 2001 Jul 19;31(1):115-30
references: 11498055
references: J Neuroimmune Pharmacol. 2011 Jun;6(2):202-15
references: 21286833
references: Mol Cell Neurosci. 2011 Jun;47(2):154-65
references: 21504794
references: EMBO J. 2009 Mar 18;28(6):697-710
references: 19197241
references: Science. 2006 Feb 17;311(5763):1008-12
references: 16484497
references: J Biol Chem. 2006 Feb 17;281(7):4423-33
references: 16356933
references: J Neurochem. 2007 Oct;103(2):439-55
references: 17897354
references: Mol Cell Neurosci. 2010 May;44(1):94-108
references: 20197093
references: Front Biosci. 2008 Jan 01;13:2484-94
references: 17981728
references: J Neuroimmune Pharmacol. 2009 Dec;4(4):430-47
references: 19768553
references: Antiviral Res. 2008 Aug;79(2):136-41
references: 18378326
references: Science. 1999 Oct 22;286(5440):785-90
references: 10531066
references: Trends Cell Biol. 2012 Mar;22(3):169-75
references: 22189166
references: Cell Death Dis. 2010;1:e77
references: 21170291
references: J Biol Chem. 2003 Apr 25;278(17):15297-303
references: 12586839
references: J Neurosci. 2006 Jan 11;26(2):440-7
references: 16407541
references: Biotechnol Annu Rev. 2005;11:127-52
references: 16216776
references: Curr Top Dev Biol. 2005;69:239-66
references: 16243602
references: Transl Psychiatry. 2011 Jul 19;1:e22
references: 22832524
references: J Biol Chem. 2008 Apr 18;283(16):10318-29
references: 18073218
references: Mol Cell Biol. 1999 Jan;19(1):21-30
references: 9858528
references: Annu Rev Neurosci. 2008;31:563-90
references: 18558867
references: Nat Rev Neurosci. 2010 May;11(5):316-28
references: 20404840
references: Microbes Infect. 2006 Apr;8(5):1347-57
references: 16697675
references: J Neuroimmune Pharmacol. 2006 Jun;1(2):138-51
references: 18040780
references: J Cell Biochem. 2009 Jun 1;107(3):400-7
references: 19343785
references: Neuron. 2008 Dec 26;60(6):1022-38
references: 19109909
references: J Neurosci. 2009 May 20;29(20):6700-9
references: 19458239
references: Brain Res Dev Brain Res. 2000 Apr 14;120(2):233-43
references: 10775775
references: J Neurosci. 2005 May 11;25(19):4823-34
references: 15888658
references: Retrovirology. 2010 Apr 07;7:30
references: 20374632
references: Trends Biochem Sci. 2002 Jan;27(1):40-7
references: 11796223
references: J Neurooncol. 2012 Apr;107(2):247-56
references: 22052333