Multiple functions of the first EGF domain in matrilin-3: Secretion and endoplasmic reticulum stress

Wang,Yi-Chun; Liu,Jing-Shi; Chen,Jun-Yi; Wu,Sheng-Qi; Wang,Gui-Rong; Nie,Jing; Zhang,Shu-Kun; Guo,Qu-Lian; Luo,Jun-Ming

doi:10.3892/ijmm.2015.2377

Multiple functions of the first EGF domain in matrilin-3: Secretion and endoplasmic reticulum stress

Authors:
- Yi-Chun Wang
- Jing-Shi Liu
- Jun-Yi Chen
- Sheng-Qi Wu
- Gui-Rong Wang
- Jing Nie
- Shu-Kun Zhang
- Qu-Lian Guo
- Jun-Ming Luo
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Affiliations: Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China, Department of Critical Care Medicine, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China, Central Laboratory, The Affiliated Cancer Hospital of Xiangya Medical School, Central South University, Changsha, Hunan 410013, P.R. China, Department of Surgery, SUNY Upstate Medical University College of Medicine, Syracuse, NY 13210, USA, Department of Pathology, Qinghai People's Provincial Hospital, Xining, Qinghai 810007, P.R. China
Published online on: October 15, 2015 https://doi.org/10.3892/ijmm.2015.2377
Pages: 1648-1656

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Abstract

Mutations in matrilin-3 are associated with common skeletal diseases, such as hand osteoarthritis (HOA), as well as rare chondrodysplasias, such as multiple epiphyseal dysplasia (MED) and spondyloepimetaphyseal dysplasia (SEMD). In the present study, we constructed the mutations R116W [at the von Willebrand factor, type A (vWFA) domain], T298M [at the first epidermal growth factor (EGF) domain] and C299S (at the first EGF domain), according to the mouse sequence, which are associated with human MED, HOA and SEMD, respectively, by overlap extension PCR and inserted them into an expression vector (pcDNA3.1/v5-His). We transfected these contructs into the COS-1 or MCT cells, and the results revealed that the HOA-related matrilin-3 mutation (T298M) leads to a high expression level of growth arrest DNA damage-inducible gene 153 (GADD153, also known as CHOP; an endoplasmic reticulum stress marker), as shown by western blot analysis and does not significantly affect protein secretion, as shown by immunofluorescence staining; however, osteochondroplasia, i.e., MED-related (R116W) and SEMD-related (C299S) mutations lead to both high levels of GADD153 expression and protein trafficking into the cytoplasm and form multiple vacuoles in cells, which in turn leads to insufficient protein secretion.

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1	Li L, Zhang L, Shao Y, Wang G, Gong R, Wang Z, Peng J, Wang S, Genochio D, Zhao B and Luo J: Distinct roles of two alternative splice variants of matrilin-2 in protein oligomerization and proteolysis. Mol Med Rep. 6:1204–1210. 2012.PubMed/NCBI
2	Krieg T and LeRoy EC: Diseases of the extracellular matrix. J Mol Med Berl. 76:224–225. 1998. View Article : Google Scholar : PubMed/NCBI
3	Mateos J, De la Fuente A, Lesende-Rodriguez I, Fernández-Pernas P, Arufe MC and Blanco FJ: Lamin A deregulation in human mesenchymal stem cells promotes an impairment in their chondrogenic potential and imbalance in their response to oxidative stress. Stem Cell Res (Amst). 11:1137–1148. 2013. View Article : Google Scholar
4	Ankam S, Teo BK, Kukumberg M and Yim EK: High throughput screening to investigate the interaction of stem cells with their extracellular microenvironment. Organogenesis. 9:128–142. 2013. View Article : Google Scholar : PubMed/NCBI
5	Chen Q, Zhang Y, Johnson DM and Goetinck PF: Assembly of a novel cartilage matrix protein filamentous network: molecular basis of differential requirement of von Willebrand factor A domains. Mol Biol Cell. 10:2149–2162. 1999. View Article : Google Scholar : PubMed/NCBI
6	Frank S, Schulthess T, Landwehr R, Lustig A, Mini T, Jenö P, Engel J and Kammerer RA: Characterization of the matrilin coiled-coil domains reveals seven novel isoforms. J Biol Chem. 277:19071–19079. 2002. View Article : Google Scholar : PubMed/NCBI
7	Klatt AR, Becker AK, Neacsu CD, Paulsson M and Wagener R: The matrilins: modulators of extracellular matrix assembly. Int J Biochem Cell Biol. 43:320–330. 2011. View Article : Google Scholar
8	Paulsson M, Piecha D, Segat D, Smyth N and Wagener R: The matrilins: a growing family of A-domain-containing proteins. Biochem Soc Trans. 27:824–826. 1999. View Article : Google Scholar
9	Piecha D, Muratoglu S, Mörgelin M, Hauser N, Studer D, Kiss I, Paulsson M and Deák F: Matrilin-2, a large, oligomeric matrix protein, is expressed by a great variety of cells and forms fibrillar networks. J Biol Chem. 274:13353–13361. 1999. View Article : Google Scholar : PubMed/NCBI
10	Whittaker CA and Hynes RO: Distribution and evolution of von Willebrand/integrin A domains: widely dispersed domains with roles in cell adhesion and elsewhere. Mol Biol Cell. 13:3369–3387. 2002. View Article : Google Scholar : PubMed/NCBI
11	Luo J and Wan Y: Tightly regulated distribution of family members of proteins is related to social property in the open body system (Review). Int J Mol Med. 17:411–418. 2006.PubMed/NCBI
12	Belluoccio D, Schenker T, Baici A and Trueb B: Characterization of human matrilin-3 (MATN3). Genomics. 53:391–394. 1998. View Article : Google Scholar : PubMed/NCBI
13	Zhang Y and Chen Q: Changes of matrilin forms during endochondral ossification. Molecular basis of oligomeric assembly. J Biol Chem. 275:32628–32634. 2000. View Article : Google Scholar : PubMed/NCBI
14	van der Weyden L, Wei L, Luo J, Yang X, Birk DE, Adams DJ, Bradley A and Chen Q: Functional knockout of the matrilin-3 gene causes premature chondrocyte maturation to hypertrophy and increases bone mineral density and osteoarthritis. Am J Pathol. 169:515–527. 2006. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Wang ZK, Luo JM, Kanbe K and Chen Q: Multiple functions of the von Willebrand Factor A domain in matrilins: secretion, assembly, and proteolysis. J Orthop Surg. 3:212008. View Article : Google Scholar :
16	Chapman KL, Mortier GR, Chapman K, Loughlin J, Grant ME and Briggs MD: Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nat Genet. 28:393–396. 2001. View Article : Google Scholar : PubMed/NCBI
17	Jackson GC, Barker FS, Jakkula E, Czarny-Ratajczak M, Mäkitie O, Cole WG, Wright MJ, Smithson SF, Suri M, Rogala P, et al: Missense mutations in the beta strands of the single A-domain of matrilin-3 result in multiple epiphyseal dysplasia. J Med Genet. 41:52–59. 2004. View Article : Google Scholar : PubMed/NCBI
18	Mäkitie O, Mortier GR, Czarny-Ratajczak M, Wright MJ, Suri M, Rogala P, Freund M, Jackson GC, Jakkula E, Ala-Kokko L, et al: Clinical and radiographic findings in multiple epiphyseal dysplasia caused by MATN3 mutations: description of 12 patients. Am J Med Genet A. 125A:278–284. 2004. View Article : Google Scholar : PubMed/NCBI
19	Mabuchi A, Haga N, Maeda K, Nakashima E, Manabe N, Hiraoka H, Kitoh H, Kosaki R, Nishimura G, Ohashi H and Ikegawa S: Novel and recurrent mutations clustered in the von Willebrand factor A domain of MATN3 in multiple epiphyseal dysplasia. Hum Mutat. 24:439–440. 2004. View Article : Google Scholar : PubMed/NCBI
20	Cotterill SL, Jackson GC, Leighton MP, Wagener R, Mäkitie O, Cole WG and Briggs MD: Multiple epiphyseal dysplasia mutations in MATN3 cause misfolding of the A-domain and prevent secretion of mutant matrilin-3. Hum Mutat. 26:557–565. 2005. View Article : Google Scholar : PubMed/NCBI
21	Wouters MA, Rigoutsos I, Chu CK, Feng LL, Sparrow DB and Dunwoodie SL: Evolution of distinct EGF domains with specific functions. Protein Sci. 14:1091–1103. 2005. View Article : Google Scholar : PubMed/NCBI
22	Rao Z, Handford P, Mayhew M, Knott V, Brownlee GG and Stuart D: The structure of a Ca²⁺-binding epidermal growth factor-like domain: its role in protein-protein interactions. Cell. 82:131–141. 1995. View Article : Google Scholar : PubMed/NCBI
23	Borochowitz ZU, Scheffer D, Adir V, Dagoneau N, Munnich A and Cormier-Daire V: Spondylo-epi-metaphyseal dysplasia (SEMD) matrilin 3 type: homozygote matrilin 3 mutation in a novel form of SEMD. J Med Genet. 41:366–372. 2004. View Article : Google Scholar : PubMed/NCBI
24	Stefánsson SE, Jónsson H, Ingvarsson T, Manolescu I, Jónsson HH, Olafsdóttir G, Pálsdóttir E, Stefánsdóttir G, Sveinbjörnsdóttir G, Frigge ML, et al: Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. Am J Hum Genet. 72:1448–1459. 2003. View Article : Google Scholar : PubMed/NCBI
25	Zhang S, Peng J, Guo Y, Javidiparsijani S, Wang G, Wang Y, Liu H, Liu J and Luo J: Matrilin-2 is a widely distributed extracellular matrix protein and a potential biomarker in the early stage of osteoarthritis in articular cartilage. Biomed Res Int. 2014:9861272014.PubMed/NCBI
26	Wei F, Moore DC, Wei L, Li Y, Zhang G, Wei X, Lee JK and Chen Q: Attenuation of osteoarthritis via blockade of the SDF-1/CXCR4 signaling pathway. Arthritis Res Ther. 14:R1772012. View Article : Google Scholar : PubMed/NCBI
27	Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, et al National Arthritis Data Workgroup: Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 58:26–35. 2008. View Article : Google Scholar : PubMed/NCBI
28	Otten C, Wagener R, Paulsson M and Zaucke F: Matrilin-3 mutations that cause chondrodysplasias interfere with protein trafficking while a mutation associated with hand osteoarthritis does not. J Med Genet. 42:774–779. 2005. View Article : Google Scholar : PubMed/NCBI
29	Liu H, Qian J, Wang F, Sun X, Xu X, Xu W and Zhang X and Zhang X: Expression of two endoplasmic reticulum stress markers, GRP78 and GADD153, in rat retinal detachment model and its implication. Eye (Lond). 24:137–144. 2010. View Article : Google Scholar
30	Feng LJ, Jiang TC, Zhou CY, Yu CL, Shen YJ, Li J and Shen YX: Activated macrophage-like synoviocytes are resistant to endoplasmic reticulum stress-induced apoptosis in antigen-induced arthritis. Inflamm Res. 63:335–346. 2014. View Article : Google Scholar : PubMed/NCBI
31	Carlisle RE, Brimble E, Werner KE, Cruz GL, Ask K, Ingram AJ and Dickhout JG: 4-Phenylbutyrate inhibits tunicamycin-induced acute kidney injury via CHOP/GADD153 repression. PLoS One. 9:e846632014. View Article : Google Scholar : PubMed/NCBI
32	Downing AK, Knott V, Werner JM, Cardy CM, Campbell ID and Handford PA: Solution structure of a pair of calcium-binding epidermal growth factor-like domains: implications for the Marfan syndrome and other genetic disorders. Cell. 85:597–605. 1996. View Article : Google Scholar : PubMed/NCBI
33	Bork P, Downing AK, Kieffer B and Campbell ID: Structure and distribution of modules in extracellular proteins. Q Rev Biophys. 29:119–167. 1996. View Article : Google Scholar : PubMed/NCBI
34	Vranka J, Mokashi A, Keene DR, Tufa S, Corson G, Sussman M, Horton WA, Maddox K, Sakai L and Bächinger HP: Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia. Matrix Biol. 20:439–450. 2001. View Article : Google Scholar : PubMed/NCBI
35	Hecht JT, Makitie O, Hayes E, Haynes R, Susic M, Montufar-Solis D, Duke PJ and Cole WG: Chondrocyte cell death and intracellular distribution of COMP and type IX collagen in the pseudoachondroplasia growth plate. J Orthop Res. 22:759–767. 2004. View Article : Google Scholar : PubMed/NCBI
36	Mann HH, Ozbek S, Engel J, Paulsson M and Wagener R: Interactions between the cartilage oligomeric matrix protein and matrilins. Implications for matrix assembly and the pathogenesis of chondrodysplasias. J Biol Chem. 279:25294–25298. 2004. View Article : Google Scholar : PubMed/NCBI
37	Oyadomari S and Mori M: Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11:381–389. 2004. View Article : Google Scholar
38	Prasanthi JRP, Larson T, Schommer J and Ghribi O: Silencing GADD153/CHOP gene expression protects against Alzheimer's disease-like pathology induced by 27-hydroxycholesterol in rabbit hippocampus. PLoS One. 6:e264202011. View Article : Google Scholar : PubMed/NCBI