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Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse.

Wilson DG, Phamluong K, Li L, Sun M, Cao TC, Liu PS, Modrusan Z, Sandoval WN, Rangell L, Carano RA, Peterson AS, Solloway MJ - J. Cell Biol. (2011)

Bottom Line: These changes are associated with intracellular accumulation of collagen and the induction of a strong unfolded protein response, primarily within the developing skeleton.Chondrocyte maturation and bone mineralization are severely compromised in Mia3- embryos, leading to dwarfism and neonatal lethality.Thus, Mia3's role in protein secretion is much broader than previously realized, and it may, in fact, be required for the efficient secretion of all collagen molecules in higher organisms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.

ABSTRACT
Melanoma inhibitory activity member 3 (MIA3/TANGO1) [corrected] is an evolutionarily conserved endoplasmic reticulum resident transmembrane protein. Recent in vitro studies have shown that it is required for the loading of collagen VII, but not collagen I, into COPII-coated transport vesicles. In this paper, we show that mice lacking Mia3 are defective for the secretion of numerous collagens, including collagens I, II, III, IV, VII, and IX, from chondrocytes, fibroblasts, endothelial cells, and mural cells. Collagen deposition by these cell types is abnormal, and extracellular matrix composition is compromised. These changes are associated with intracellular accumulation of collagen and the induction of a strong unfolded protein response, primarily within the developing skeleton. Chondrocyte maturation and bone mineralization are severely compromised in Mia3- embryos, leading to dwarfism and neonatal lethality. Thus, Mia3's role in protein secretion is much broader than previously realized, and it may, in fact, be required for the efficient secretion of all collagen molecules in higher organisms.

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A schematic for the interaction between Mia3 and the UPR machinery in regulating collagen metabolism as modeled in chondrocytes. (A) In wt animals, the normally low levels of UPR regulators are sufficient to handle the increase in protein load during chondrocyte maturation. (B) The loss of Mia3 rapidly leads to buildup and retention of collagen within the ER and initiates a strong and sustained UPR that is sufficient to slow cellular differentiation and prevent generalized apoptosis.
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fig9: A schematic for the interaction between Mia3 and the UPR machinery in regulating collagen metabolism as modeled in chondrocytes. (A) In wt animals, the normally low levels of UPR regulators are sufficient to handle the increase in protein load during chondrocyte maturation. (B) The loss of Mia3 rapidly leads to buildup and retention of collagen within the ER and initiates a strong and sustained UPR that is sufficient to slow cellular differentiation and prevent generalized apoptosis.

Mentions: We have found that loss of function of the ER-resident protein Mia3 leads to developmental defects primarily affecting the embryonic skeleton and skin (Fig. 9). We demonstrate that in mutant embryos and primary cell lysates, secretion of numerous collagens, including collagens I, II, III, IV, VII, and IX, is disrupted, most likely because of defective export from the ER. Collagen fibrils, though dispersed and diminished in number, are present in the knockout ECM, and a reduced amount of ECM-associated collagen is discernible by Western blotting and immunofluorescence. This reduction, in turn, leads to a delay in chondrogenesis, and the embryonic phenotype resembles an amalgam of chondrodysplastic disorders arising from defective collagen folding, deposition, and/or maturation.


Global defects in collagen secretion in a Mia3/TANGO1 knockout mouse.

Wilson DG, Phamluong K, Li L, Sun M, Cao TC, Liu PS, Modrusan Z, Sandoval WN, Rangell L, Carano RA, Peterson AS, Solloway MJ - J. Cell Biol. (2011)

A schematic for the interaction between Mia3 and the UPR machinery in regulating collagen metabolism as modeled in chondrocytes. (A) In wt animals, the normally low levels of UPR regulators are sufficient to handle the increase in protein load during chondrocyte maturation. (B) The loss of Mia3 rapidly leads to buildup and retention of collagen within the ER and initiates a strong and sustained UPR that is sufficient to slow cellular differentiation and prevent generalized apoptosis.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3105544&req=5

fig9: A schematic for the interaction between Mia3 and the UPR machinery in regulating collagen metabolism as modeled in chondrocytes. (A) In wt animals, the normally low levels of UPR regulators are sufficient to handle the increase in protein load during chondrocyte maturation. (B) The loss of Mia3 rapidly leads to buildup and retention of collagen within the ER and initiates a strong and sustained UPR that is sufficient to slow cellular differentiation and prevent generalized apoptosis.
Mentions: We have found that loss of function of the ER-resident protein Mia3 leads to developmental defects primarily affecting the embryonic skeleton and skin (Fig. 9). We demonstrate that in mutant embryos and primary cell lysates, secretion of numerous collagens, including collagens I, II, III, IV, VII, and IX, is disrupted, most likely because of defective export from the ER. Collagen fibrils, though dispersed and diminished in number, are present in the knockout ECM, and a reduced amount of ECM-associated collagen is discernible by Western blotting and immunofluorescence. This reduction, in turn, leads to a delay in chondrogenesis, and the embryonic phenotype resembles an amalgam of chondrodysplastic disorders arising from defective collagen folding, deposition, and/or maturation.

Bottom Line: These changes are associated with intracellular accumulation of collagen and the induction of a strong unfolded protein response, primarily within the developing skeleton.Chondrocyte maturation and bone mineralization are severely compromised in Mia3- embryos, leading to dwarfism and neonatal lethality.Thus, Mia3's role in protein secretion is much broader than previously realized, and it may, in fact, be required for the efficient secretion of all collagen molecules in higher organisms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biology, Genentech, South San Francisco, CA 94080, USA.

ABSTRACT
Melanoma inhibitory activity member 3 (MIA3/TANGO1) [corrected] is an evolutionarily conserved endoplasmic reticulum resident transmembrane protein. Recent in vitro studies have shown that it is required for the loading of collagen VII, but not collagen I, into COPII-coated transport vesicles. In this paper, we show that mice lacking Mia3 are defective for the secretion of numerous collagens, including collagens I, II, III, IV, VII, and IX, from chondrocytes, fibroblasts, endothelial cells, and mural cells. Collagen deposition by these cell types is abnormal, and extracellular matrix composition is compromised. These changes are associated with intracellular accumulation of collagen and the induction of a strong unfolded protein response, primarily within the developing skeleton. Chondrocyte maturation and bone mineralization are severely compromised in Mia3- embryos, leading to dwarfism and neonatal lethality. Thus, Mia3's role in protein secretion is much broader than previously realized, and it may, in fact, be required for the efficient secretion of all collagen molecules in higher organisms.

Show MeSH
Related in: MedlinePlus