title: Secretion of cartilage oligomeric matrix protein is affected by the signal peptide.
abstract: Cartilage oligomeric matrix protein (COMP) is a secreted glycoprotein found in the extracellular matrices of skeletal tissues. Mutations associated with two human skeletal dysplasias, pseudoachondroplasia and multiple epiphyseal dysplasia, disturb COMP secretion leading to intracellular accumulation of mutant COMP, especially in chondrocytes. Here we show that the manifestation of this secretory defect is dramatically influenced by the signal peptide that targets COMP for secretion. The comparison of wild type and mutant COMP secretion directed by the COMP or BM40 signal peptide in HEK-293 cells and rat chondrosarcoma cells revealed that the BM40 signal peptide substantially enhances secretion of mutant COMP that accumulates in endoplasmic reticulum-like structures when targeted by its own signal peptide. Additionally, we demonstrate that mutant COMP forms mixed pentamers with wild type COMP. Our findings suggest that the secretory defect in pseudoachondroplasia and multiple epiphyseal dysplasia is not specific for chondrocytes, nor does it require interaction of mutant COMP with other matrix proteins prior to transport from the cell. They also imply a previously unappreciated role for the signal peptide in the regulation of protein secretion beyond targeting to the endoplasmic reticulum.
authors.affiliation: Research Center, Shriners Hospitals for Children, Portland, Oregon 97239, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Holden
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Lunstrum
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Bächinger
authors.forename: William A
authors.initials: WA
authors.lastname: Horton
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism; D064236:Cartilage Oligomeric Matrix Protein; D002460:Cell Line; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000378:metabolism; D002813:Chondrosarcoma / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism*; D006639:Histidine / Q000737:chemistry; D006801:Humans; D064235:Matrilin Proteins; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D009154:Mutation; D010009:Osteochondrodysplasias / Q000473:pathology; D017510:Protein Folding; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C577540:Matn1 protein, mouse; D064235:Matrilin Proteins; D021382:Protein Sorting Signals; D011994:Recombinant Proteins; C577553:TSP5 protein, human; D006639:Histidine; D012313:RNA