title: Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes.
abstract: Accumulation of proteins in the endoplasmic reticulum (ER) typically induces stress and initiates the unfolded protein response (UPR) to facilitate recovery. If homeostasis is not restored, apoptosis is induced. However, adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress. We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca2)-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin. Although thapsigargin triggers UPR activation, instead of Perk-mediated phosphorylation of eIF2α, in Oca2-null melanocytes, eIF2α was rapidly dephosphorylated upon treatment. Dephosphorylation was mediated by the Gadd34-PP1α phosphatase complex. Gadd34-complex inhibition blocked eIF2α dephosphorylation and significantly increased Oca2-null melanocyte sensitivity to thapsigargin. Thus, Oca2-null melanocytes adapt to acute ER stress by disruption of pro-apoptotic Perk signaling, which promotes cell survival. This is the first study to demonstrate rapid eIF2α dephosphorylation as an adaptive mechanism to ER stress.
authors: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA.
authors: Tsing
authors: T
authors: Cheng
authors: Seth J
authors: SJ
authors: Orlow
authors: Prashiela
authors: P
authors: Manga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism; D006143:Guanabenz / Q000494:pharmacology; D008544:Melanocytes / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019284:Thapsigargin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D004722:Endoribonucleases; D006143:Guanabenz; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D054645:Protein Phosphatase 1; D017346:Protein Serine-Threonine Kinases; D019284:Thapsigargin; D019892:eIF-2 Kinase; C076239:P protein, mouse; C510185:Ern1 protein, mouse; C513256:Ppp1r15a protein, mouse
keywords: ER stress; eIF2α; melanocyte; oculocutaneous albinism type 2; unfolded protein response
references: J Biol Chem. 2004 May 7;279(19):20108-17
references: 14978030
references: FASEB J. 2001 Oct;15(12):2149-61
references: 11641241
references: Science. 2007 Nov 9;318(5852):944-9
references: 17991856
references: Pigment Cell Melanoma Res. 2008 Jun;21(3):358-67
references: 18476909
references: Int J Cancer. 1987 Mar 15;39(3):414-8
references: 3102392
references: Genes Dev. 2004 Dec 15;18(24):3066-77
references: 15601821
references: Carcinogenesis. 2007 Nov;28(11):2328-36
references: 17652336
references: Mol Cell Biol. 2001 Feb;21(4):1249-59
references: 11158311
references: Histopathology. 2009 Mar;54(4):462-70
references: 19309398
references: Methods. 2005 Apr;35(4):395-416
references: 15804613
references: Science. 2011 Apr 1;332(6025):91-4
references: 21385720
references: Eur J Immunol. 2011 Feb;41(2):491-502
references: 21268018
references: J Cell Sci. 2002 Jan 15;115(Pt 2):241-56
references: 11839776
references: Pigment Cell Melanoma Res. 2010 Oct;23(5):627-34
references: 20444203
references: J Invest Dermatol. 1997 Jan;108(1):30-4
references: 8980282
references: Mol Biol Cell. 2002 Dec;13(12):4206-20
references: 12475946
references: Mol Cell Biol. 2000 Sep;20(18):6755-67
references: 10958673
references: Drugs. 1983 Sep;26(3):212-29
references: 6352237
references: Pigment Cell Res. 2002 Jun;15(3):217-24
references: 12028586
references: Mol Cell Biol. 2001 Oct;21(20):6841-50
references: 11564868
references: Mol Biol Cell. 2002 Jun;13(6):1953-64
references: 12058062
references: Nat Genet. 2012 May 06;44(6):676-80
references: 22561518
references: Cell. 2001 Dec 28;107(7):881-91
references: 11779464
references: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11269-74
references: 15277680
references: Mol Cell Biol. 2003 Feb;23(4):1292-303
references: 12556489
references: Nat Immunol. 2008 May;9(5):533-41
references: 18362886
references: J Invest Dermatol. 2012 Nov;132(11):2601-9
references: 22696056
references: J Cell Biol. 2004 Jan 19;164(2):291-300
references: 14718519
references: PLoS One. 2008 Apr 23;3(4):e1981
references: 18431471
references: Curr Opin Neurobiol. 2009 Oct;19(5):505-10
references: 19744850
references: N Engl J Med. 1994 Feb 24;330(8):529-34
references: 8302318
references: Cell. 2002 Jun 14;109(6):707-18
references: 12086670
references: Cell Signal. 2013 Jan;25(1):144-9
references: 23010535
references: Nature. 2002 Jan 3;415(6867):92-6
references: 11780124
references: PLoS One. 2009;4(1):e4170
references: 19137072