Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia.
Selective intracellular retention of extracellular matrix proteins and chaperones associated with pseudoachondroplasia.
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DOI：
10.1016/s0945-053x(01)00148-2
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发表时间：
2001-11
期刊：
影响因子：
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通讯作者：
Janice A. Vranka;Asawari Mokashi;Asawari Mokashi;D. Keene;S. Tufa;G. Corson;M. Sussman;W. Horton;W. Horton;Kerry Maddox;Kerry Maddox;L. Sakai;L. Sakai;H. Bächinger;H. Bächinger
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作者：
Janice A. Vranka;Asawari Mokashi;Asawari Mokashi;D. Keene;S. Tufa;G. Corson;M. Sussman;W. Horton;W. Horton;Kerry Maddox;Kerry Maddox;L. Sakai;L. Sakai;H. Bächinger;H. Bächinger
软骨寡聚基质蛋白 (COMP) 基因突变会导致假性软骨发育不全 (PSACH)，这是一种以早发性骨关节炎和身材矮小为特征的软骨发育不良。 COMP 是一种分泌型五聚体糖蛋白，属于血小板反应蛋白家族。我们在诊断为 PSACH 的患者中发现了一种新的错义突变，该突变用甘氨酸取代了 COMP 的血小板反应蛋白 (TSP) 3 型钙结合结构域中的天冬氨酸残基。免疫组织化学和免疫电子显微镜均显示 COMP 在 PSACH 软骨细胞特征性增大的 rER 包涵体中异常保留，以及纤维调节蛋白、核心蛋白聚糖和 IX、XI 和 XII 型胶原的保留。聚集蛋白聚糖以及II型和VI型胶原蛋白不保留在相同细胞内的细胞内。除了选择性细胞外基质成分外，伴侣蛋白 HSP47、蛋白质二硫键异构酶 (PDI) 和钙联蛋白在 PSACH 软骨细胞的 rER 囊泡中定位水平升高，表明它们可能在突变 COMP 分子的细胞保留中发挥作用。 PSACH 软骨细胞中异常的 rER 内含物是否是伴侣介导的突变 COMP 保留的直接结果，还是由于选择性细胞内蛋白质相互作用（这反过来可能导致 rER 内聚集）所致，目前尚不清楚。然而，我们的数据表明，突变型 COMP 分子的保留导致 ECM 分子和分子伴侣的选择性保留，表明基质分子存在不同的分泌途径或 ER 分选机制，这是由它们与各种分子伴侣的关联介导的过程。
Mutations in the cartilage oligomeric matrix protein (COMP) gene result in pseudoachondroplasia (PSACH), which is a chondrodysplasia characterized by early-onset osteoarthritis and short stature. COMP is a secreted pentameric glycoprotein that belongs to the thrombospondin family of proteins. We have identified a novel missense mutation which substitutes a glycine for an aspartic acid residue in the thrombospondin (TSP) type 3 calcium-binding domain of COMP in a patient diagnosed with PSACH. Immunohistochemistry and immunoelectron microscopy both show abnormal retention of COMP within characteristically enlarged rER inclusions of PSACH chondrocytes, as well as retention of fibromodulin, decorin and types IX, XI and XII collagen. Aggrecan and types II and VI collagen were not retained intracellularly within the same cells. In addition to selective extracellular matrix components, the chaperones HSP47, protein disulfide isomerase (PDI) and calnexin were localized at elevated levels within the rER vesicles of PSACH chondrocytes, suggesting that they may play a role in the cellular retention of mutant COMP molecules. Whether the aberrant rER inclusions in PSACH chondrocytes are a direct consequence of chaperone-mediated retention of mutant COMP or are otherwise due to selective intracellular protein interactions, which may in turn lead to aggregation within the rER, is unclear. However, our data demonstrate that retention of mutant COMP molecules results in the selective retention of ECM molecules and molecular chaperones, indicating the existence of distinct secretory pathways or ER-sorting mechanisms for matrix molecules, a process mediated by their association with various molecular chaperones.