title: Armet/Manf and Creld2 are components of a specialized ER stress response provoked by inappropriate formation of disulphide bonds: implications for genetic skeletal diseases.
abstract: Mutant matrilin-3 (V194D) forms non-native disulphide bonded aggregates in the rER of chondrocytes from cell and mouse models of multiple epiphyseal dysplasia (MED). Intracellular retention of mutant matrilin-3 causes endoplasmic reticulum (ER) stress and induces an unfolded protein response (UPR) including the upregulation of two genes recently implicated in ER stress: Armet and Creld2. Nothing is known about the role of Armet and Creld2 in human genetic diseases. In this study, we used a variety of cell and mouse models of chondrodysplasia to determine the genotype-specific expression profiles of Armet and Creld2. We also studied their interactions with various mutant proteins and investigated their potential roles as protein disulphide isomerases (PDIs). Armet and Creld2 were up-regulated in cell and/or mouse models of chondrodysplasias caused by mutations in Matn3 and Col10a1, but not Comp. Intriguingly, both Armet and Creld2 were also secreted into the ECM of these disease models following ER stress. Armet and Creld2 interacted with mutant matrilin-3, but not with COMP, thereby validating the genotype-specific expression. Substrate-trapping experiments confirmed Creld2 processed PDI-like activity, thus identifying a putative functional role. Finally, alanine substitution of the two terminal cysteine residues from the A-domain of V194D matrilin-3 prevented aggregation, promoted mutant protein secretion and reduced the levels of Armet and Creld2 in a cell culture model. We demonstrate that Armet and Creld2 are genotype-specific ER stress response proteins with substrate specificities, and that aggregation of mutant matrilin-3 is a key disease trigger in MED that could be exploited as a potential therapeutic target.
authors: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, The University of Manchester, Manchester M13 9PT, England.
authors: Claire L
authors: CL
authors: Hartley
authors: Sarah
authors: S
authors: Edwards
authors: Lorna
authors: L
authors: Mullan
authors: Peter A
authors: PA
authors: Bell
authors: Maryline
authors: M
authors: Fresquet
authors: Raymond P
authors: RP
authors: Boot-Handford
authors: Michael D
authors: MD
authors: Briggs
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019902:Chondrocytes / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D064235:Matrilin Proteins / Q000235:genetics; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics*; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology
chemical_list: C507070:CRELD2 protein, human; D015815:Cell Adhesion Molecules; C570620:Col10a1 protein, mouse; D024121:Collagen Type X; D016326:Extracellular Matrix Proteins; C099695:MANF protein, human; D064235:Matrilin Proteins; D009414:Nerve Growth Factors
references: Annu Rev Biochem. 2007;76:629-45
references: 17263661
references: Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16348-53
references: 22988091
references: Hum Mol Genet. 1994 Feb;3(2):303-7
references: 8004099
references: J Cell Biol. 1996 May;133(3):517-27
references: 8636228
references: BMC Cell Biol. 2010 Jul 26;11:59
references: 20659334
references: Int J Biochem Cell Biol. 2011 Mar;43(3):320-30
references: 21163365
references: Mol Cell Proteomics. 2012 Sep;11(9):710-23
references: 22665516
references: J Cell Biol. 2007 Dec 17;179(6):1193-204
references: 18086916
references: Biochem Biophys Res Commun. 2009 Sep 25;387(3):504-10
references: 19615339
references: FEBS J. 2007 Oct;274(20):5223-34
references: 17892489
references: Dev Neurobiol. 2010 Apr;70(5):360-71
references: 20186704
references: Biochem J. 1999 Apr 1;339 ( Pt 1):1-10
references: 10085220
references: Hum Mutat. 2005 Dec;26(6):557-65
references: 16287128
references: Hum Mutat. 2004 Nov;24(5):439-40
references: 15459972
references: Hum Mutat. 2012 Jan;33(1):144-57
references: 21922596
references: J Biol Chem. 2005 Apr 22;280(16):15544-52
references: 15695517
references: Hum Mol Genet. 2007 Sep 1;16(17):2072-88
references: 17588960
references: Hum Mol Genet. 2007 May 15;16(10):1201-15
references: 17403716
references: Cell Stress Chaperones. 2010 Nov;15(6):835-49
references: 20428984
references: Biochem Biophys Res Commun. 1997 Nov 7;240(1):36-40
references: 9367877
references: Am J Med Genet A. 2011 May;155A(5):943-68
references: 21438135
references: Br J Dermatol. 1998 Aug;139(2):325-31
references: 9767254
references: Trends Pharmacol Sci. 2013 Feb;34(2):119-25
references: 23380248
references: J Biol Chem. 2006 Oct 27;281(43):32587-95
references: 16928687
references: J Clin Invest. 2002 Nov;110(10):1389-98
references: 12438434
references: J Biol Chem. 2002 Apr 12;277(15):12516-24
references: 11805116
references: PLoS Biol. 2007 Mar;5(3):e44
references: 17298185
references: PLoS One. 2011;6(9):e24600
references: 21935428
references: J Mol Cell Cardiol. 2011 Oct;51(4):512-7
references: 20970425
references: EMBO J. 2007 Jan 10;26(1):28-40
references: 17170699
references: Am J Pathol. 2003 Jul;163(1):101-10
references: 12819015
references: Mol Biol Cell. 2002 Oct;13(10):3369-87
references: 12388743
references: Cell Tissue Res. 2010 Jan;339(1):197-211
references: 19851784
references: EMBO Rep. 2005 Jan;6(1):28-32
references: 15643448
references: J Clin Invest. 2002 Aug;110(4):505-13
references: 12189245
references: Mol Cell Biochem. 2012 Apr;363(1-2):35-41
references: 22120531
references: Exp Cell Res. 2008 Aug 1;314(13):2454-67
references: 18561914
references: J Med Genet. 2004 Jan;41(1):52-9
references: 14729835
references: J Clin Invest. 1999 Jan;103(1):27-37
references: 9884331
references: Arthritis Rheum. 2012 May;64(5):1529-39
references: 22083516
references: Ann Neurol. 2007 Oct;62(4):390-405
references: 17886299
references: J Biol Chem. 2010 Oct 22;285(43):33567-33576
references: 20729548
references: PLoS Genet. 2009 Oct;5(10):e1000691
references: 19834559
references: Nat Genet. 2001 Aug;28(4):393-6
references: 11479597
references: Trends Cell Biol. 2004 Jan;14(1):20-8
references: 14729177
references: Cell Struct Funct. 2007;32(1):41-50
references: 17507765
references: J Med Genet. 2005 Sep;42(9):673-85
references: 16141002
references: J Comp Neurol. 2009 Jul 1;515(1):116-24
references: 19399876
references: J Neurochem. 2005 Dec;95(6):1585-96
references: 16238698
references: Orphanet J Rare Dis. 2013 Jan 14;8:11
references: 23316740
references: Hum Mol Genet. 2010 Jan 1;19(1):25-35
references: 19801575
references: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references: 17565364
references: Nat Rev Genet. 2009 Mar;10(3):173-83
references: 19204719
references: Hum Mol Genet. 2007 Jul 15;16(14):1728-41
references: 17517694
references: Hum Mutat. 2008 Feb;29(2):330
references: 18205203
references: Hum Mutat. 2012 Jan;33(1):218-31
references: 22006726