title: Identification of p58IPK as a novel neuroprotective factor for retinal neurons.
abstract: OBJECTIVE
  Endoplasmic reticulum (ER)-resident chaperone protein p58(IPK) plays a vital role in regulation of protein folding and biosynthesis. The goal of this study was to examine the role of p58(IPK) in retinal neuronal cells under normal and stressed conditions.
  
  
  METHODS
  Retinal expression of p58(IPK), retinal morphology, apoptosis, ER stress, and apoptotic gene expression were examined in p58(IPK) knockout (KO) and/or wild-type (WT) mice with or without intravitreal injection of N-methyl-D-aspartic acid (NMDA). In in vitro experiments, differentiated R28 retinal neuronal cells transduced with adenovirus encoding p58(IPK) (Ad-p58(IPK)) or control virus (Ad-LacZ) were exposed to tunicamycin (TM) or hydrogen peroxide (H2O2). Levels of ER stress, apoptosis, and cell survival were evaluated.
  
  
  RESULTS
  Chaperone protein p58(IPK) is expressed predominantly in retinal ganglion cells (RGC), inner retinal neurons, and the photoreceptor inner segments. Mice lacking p58(IPK) exhibited increased CHOP expression and loss of RGCs with aging (8-10 months). Intravitreal injection of NMDA induced retinal ER stress and increased p58(IPK) expression in WT mice; this resulted in greater ER stress and enhanced RGC apoptosis in p58(IPK) KO mice. In cultured R28 cells, overexpression of p58(IPK) significantly reduced eIF2α phosphorylation, decreased CHOP expression, and alleviated the activation of caspase-3 and PARP. Overexpression of p58(IPK) also protected against oxidative and ER stress-induced cell apoptosis. Furthermore, p58(IPK) downregulated the proapoptotic gene Bax and upregulated the antiapoptotic gene Bcl-2 expression in stressed R28 cells.
  
  
  CONCLUSIONS
  Our study has demonstrated a protective role of p58(IPK) in retinal neurons, which may act in part through a mechanism involving modulation of ER homeostasis and apoptosis, particularly under conditions of cellular stresses.
authors: Department of Ophthalmology and Biochemistry/Ross Eye Institute, University at Buffalo/SUNY, Buffalo, New York, United States SUNY Eye Institute, State University of New York, Buffalo, New York, United States.
authors: Evgenii
authors: E
authors: Boriushkin
authors: Department of Ophthalmology and Biochemistry/Ross Eye Institute, University at Buffalo/SUNY, Buffalo, New York, United States.
authors: Joshua J
authors: JJ
authors: Wang
authors: Department of Ophthalmology and Biochemistry/Ross Eye Institute, University at Buffalo/SUNY, Buffalo, New York, United States SUNY Eye Institute, State University of New York, Buffalo, New York, United States.
authors: Junhua
authors: J
authors: Li
authors: Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
authors: Guangjun
authors: G
authors: Jing
authors: SUNY Eye Institute, State University of New York, Buffalo, New York, United States Center for Hearing & Deafness, University at Buffalo, Buffalo/SUNY, New York, United States.
authors: Gail M
authors: GM
authors: Seigel
authors: Department of Ophthalmology and Biochemistry/Ross Eye Institute, University at Buffalo/SUNY, Buffalo, New York, United States.
authors: Sarah X
authors: SX
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012313:RNA / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012164:Retinal Diseases / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: C500846:Dnajc3 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D012313:RNA; D016202:N-Methylaspartate
keywords: chaperone; endoplasmic reticulum stress; neuronal cells; p58IPK
references: Cell Biol Int. 2007 May;31(5):438-43
references: 17321170
references: Proc Natl Acad Sci U S A. 1997 Jan 7;94(1):97-102
references: 8990167
references: Invest Ophthalmol Vis Sci. 2007 Aug;48(8):3729-36
references: 17652745
references: Mol Biol Cell. 2007 Sep;18(9):3681-91
references: 17567950
references: Antioxid Redox Signal. 2007 Dec;9(12):2277-93
references: 17979528
references: J Biol Chem. 2007 Nov 23;282(47):34525-34
references: 17890727
references: Brain Res. 2008 Jan 10;1188:35-43
references: 18053973
references: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2008 Feb 1;64(Pt 2):108-10
references: 18259061
references: Mol Vis. 2008;14:1122-8
references: 18568130
references: Vasc Health Risk Manag. 2008;4(1):115-22
references: 18629365
references: EMBO J. 2008 Nov 5;27(21):2862-72
references: 18923430
references: Brain Res. 2010 Jan 13;1308:158-66
references: 19853589
references: J Mol Biol. 2010 Apr 16;397(5):1307-15
references: 20184891
references: Mol Vis. 2011;17:78-84
references: 21245960
references: Methods Enzymol. 2011;490:259-70
references: 21266255
references: J Biol Chem. 2011 Feb 11;286(6):4912-21
references: 21138840
references: Biotechnol Bioeng. 2011 Dec;108(12):2777-93
references: 21809331
references: Exp Diabetes Res. 2012;2012:589589
references: 22216020
references: Neuron. 2012 Feb 9;73(3):445-52
references: 22325198
references: Mol Vis. 2014;20:301-6
references: 24644404
references: Antioxid Redox Signal. 2014 May 10;20(14):2091-106
references: 24053669
references: Prog Retin Eye Res. 2015 Mar;45:111-31
references: 25529848
references: Semin Cell Dev Biol. 1999 Oct;10(5):465-72
references: 10597629
references: J Biol Chem. 2001 Aug 31;276(35):32814-21
references: 11443130
references: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10845-50
references: 11526215
references: J Neurochem. 2001 Nov;79(4):719-25
references: 11723164
references: Mol Neurobiol. 2001 Aug-Dec;24(1-3):107-29
references: 11831548
references: J Clin Invest. 2002 Feb;109(4):525-32
references: 11854325
references: Curr Opin Ophthalmol. 1997 Apr;8(2):28-37
references: 10168354
references: Mol Vis. 1996 Apr 24;2:2
references: 9233983
references: Mol Cell Biol. 1998 Feb;18(2):859-71
references: 9447982
references: Gen Pharmacol. 1998 Mar;30(3):275-80
references: 9510074
references: Invest Ophthalmol Vis Sci. 1999 Mar;40(3):713-20
references: 10067975
references: Diabetes. 2005 Apr;54(4):1074-81
references: 15793246
references: J Clin Invest. 2005 Oct;115(10):2656-64
references: 16200199
references: J Neurochem. 2006 Jan;96(1):43-52
references: 16269013
references: EMBO Rep. 2006 Sep;7(9):880-5
references: 16953201
references: Mol Cell. 2007 Apr 13;26(1):1-14
references: 17434122
references: Mol Vis. 2007;13:578-87
references: 17438523
references: J Neurosci. 2002 Dec 15;22(24):10751-60
references: 12486168
references: Biochem Biophys Res Commun. 2003 May 9;304(3):445-54
references: 12729578
references: Curr Eye Res. 2004 Apr;28(4):257-69
references: 15259295
references: Cell Death Differ. 2004 Sep;11(9):1009-16
references: 15131590
references: Nature. 1991 Oct 24;353(6346):726-30
references: 1834945
references: Genes Dev. 1992 Mar;6(3):439-53
references: 1547942
references: Science. 1992 Sep 11;257(5076):1496-502
references: 1523409
references: Vision Res. 1994 Aug;34(15):1935-46
references: 7941395
references: J Biol Chem. 1996 Jan 19;271(3):1702-7
references: 8576172
references: J Biol Chem. 1996 Nov 8;271(45):28660-6
references: 8910500
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364