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Papers In Press, published online ahead of print August 25, 2000
Pediatrics, University of Chicago, Chicago, IL 60637
Corresponding Author: n-schwartz{at}uchicago.edu
Aggrecan is a complex multidomain macromolecule that undergoes extensive processing and posttranslational modification. A thorough understanding of the events and signals that promote translocation of aggrecan through the secretory pathway is lacking. To investigate which features of the C-terminal G3 region are necessary for successful translocation of the core protein, a number of deletion constructs based on the chick aggrecan cDNA sequence were prepared and transiently expressed in COS-1 cells and the natural host, embryonic chick chondrocytes; stable cell lines were established as well. The present results clearly establish a precise requirement for that portion of the G3 C-lectin domain encoded by exon 15 for: i) translocation from the ER to the Golgi, ii) secretion from the cell, iii) galactosylation of CS chains, iiii) generation of Ca+2 dependent galactose binding ability. Furthermore in the absence of this subdomain there is excess accumulation in the ER of expression products leading to a stress-related response involving the chaperones Grp78 and PDI, followed by degradation via an ubiquitin-proteosome pathway. All of these events in the model system faithfully mimic the naturally-occurring nanomelic mutant, which also elicits an ubiquitin-mediated degradation response due to the accumulation of the truncated core protein precursor. This study represents the first report of the mode of degradation of overexpressed or misfolded proteoglycans and suggests that although proteoglycans follow different glycosylation pathways from other glycoproteins, they are monitored by an ER surveillance system similar to that which detects other misfolded proteins.
J. Biol. Chem, 10.1074/jbc.M007585200
Submitted on August 19, 2000
Accepted on August 25, 2000
Role of the C-Terminal G3 Domain in Sorting and Secretion of Aggrecan Core Protein and Ubiquitin-Mediated Degradation of Accumlated Mutant Precursors
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