Regulation of the production of secretory proteins: intracellular degradation of newly synthesized "defective" collagen.

Publication Type	Academic Article
Authors	Berg R, Schwartz M, Crystal R
Journal	Proc Natl Acad Sci U S A
Volume	77
Issue	8
Pagination	4746-50
Date Published	08/01/1980
ISSN	0027-8424
Keywords	Collagen
Abstract	Confluent cultures of human fetal lung fibroblasts degrade approximately 10% of their newly synthesized collagen within the cell prior to secretion. This basal level of intracellular degradation could not be inhibited by colchicine or cytochalasin B, inhibitors of microtubular and microfilament function, respectively, or by N(alpha)-p-tosyl-L-lysine chloromethyl ketone, chloroquine, or NH(4)Cl, inhibitors of lysosomal enzymes. In contrast, cells in early logarithmic growth degrade approximately 30% of their newly synthesized collagen. This enhanced degradation of collagen in rapidly growing cells could be suppressed by inhibitors of lysosomal proteases and partially inhibited by disrupters of microtubular and microfilament function. A significant proportion of the collagen synthesized by these cultures contained prolyl residues that were incompletely hydroxylated. Because such collagen is "defective" (i.e., not capable of assuming a triple helical conformation), the results suggest that enhanced intracellular degradation may be a mechanism by which cells control the quality of collagen they produce. To test this hypothesis, confluent cells were incubated with the proline analog cis-4-hydroxyproline; such cells demonstrated enhanced collagen degradation that could be inhibited by agents that interfere with lysosomal, microtubular, or microfilament function. Because collagen containing cis-4-hydroxyproline cannot form a perfect triple helix, the data are consistent with the concept that defective collagen is recognized by cells and degraded prior to secretion. Thus, the proportion of newly synthesized collagen that undergoes intracellular degradation seems to be modulated, in part, by the conformation of the collagen molecule. Intracellular proteolysis may represent a means by which collagen-producing cells regulate the quality and quantity of collagen available for extracellular function. Although the exact mechanism of intracellular collagen degradation is unknown, the data presented here are consistent with a role for lysosomal proteases in this process.
DOI	10.1073/pnas.77.8.4746
PubMed ID	6933520
PubMed Central ID	PMC349923