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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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The endoplasmic reticulum is grossly distended, and collagen fibrils are reduced in knockout chondrocytes. (A–D) Comparative TEM images of wt (A and C) and Mia3 mutant (B and D) proliferative zone chondrocytes within the humerus. ER distention is clearly evident in the majority of  cells along with a concomitant reduction in extracellular collagen fibril assembly (asterisks). Nuc, nucleus.
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fig7: The endoplasmic reticulum is grossly distended, and collagen fibrils are reduced in knockout chondrocytes. (A–D) Comparative TEM images of wt (A and C) and Mia3 mutant (B and D) proliferative zone chondrocytes within the humerus. ER distention is clearly evident in the majority of cells along with a concomitant reduction in extracellular collagen fibril assembly (asterisks). Nuc, nucleus.

Mentions: To further investigate how protein accumulation affected Mia3 mutant cells, we performed transmission EM (TEM) analysis of developing chondrocytes. TEM revealed marked distension of the ER in Mia3 mutants (Fig. 7, A–D), which is consistent with ER accumulation of collagens in these highly secretory cells. Furthermore, it is well recognized that abnormal accumulation of misfolded proteins in the ER causes ER stress, which triggers the response of the ER quality control system (Ma and Hendershot, 2004). Given the distended ER revealed by TEM and immunofluorescent detection of increased and apparently aggregated collagens in mutant cells, we hypothesized that the unfolded protein response (UPR) might be induced.


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)

The endoplasmic reticulum is grossly distended, and collagen fibrils are reduced in knockout chondrocytes. (A–D) Comparative TEM images of wt (A and C) and Mia3 mutant (B and D) proliferative zone chondrocytes within the humerus. ER distention is clearly evident in the majority of  cells along with a concomitant reduction in extracellular collagen fibril assembly (asterisks). Nuc, nucleus.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig7: The endoplasmic reticulum is grossly distended, and collagen fibrils are reduced in knockout chondrocytes. (A–D) Comparative TEM images of wt (A and C) and Mia3 mutant (B and D) proliferative zone chondrocytes within the humerus. ER distention is clearly evident in the majority of cells along with a concomitant reduction in extracellular collagen fibril assembly (asterisks). Nuc, nucleus.
Mentions: To further investigate how protein accumulation affected Mia3 mutant cells, we performed transmission EM (TEM) analysis of developing chondrocytes. TEM revealed marked distension of the ER in Mia3 mutants (Fig. 7, A–D), which is consistent with ER accumulation of collagens in these highly secretory cells. Furthermore, it is well recognized that abnormal accumulation of misfolded proteins in the ER causes ER stress, which triggers the response of the ER quality control system (Ma and Hendershot, 2004). Given the distended ER revealed by TEM and immunofluorescent detection of increased and apparently aggregated collagens in mutant cells, we hypothesized that the unfolded protein response (UPR) might be induced.

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