Profibrillin-1 maturation by human dermal fibroblasts: Proteolytic processing and molecular chaperones

Debra D. Wallis, Elizabeth A. Putnam, Jill S. Cretoiu, Sonya G. Carmical, Shi Nian Cao, Gary Thomas, Dianna M. Milewicz

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Fibrillin-1 is synthesized as a proprotein that undergoes proteolytic processing in the unique C-terminal domain by a member of the PACE/furin family of endoproteases. This family of endoproteases is active in the trans-Golgi network (TGN), but metabolic labeling studies have been controversial as to whether profibrillin-1 is processed intracellularly or after secretion. This report provides evidence that profibrillin-1 processing is not an intracellular event. Bafilomycin A1 and incubation of dermal fibroblasts at 22°C were used to block secretion in the TGN to confirm that profibrillin-1 processing did not occur in this compartment. Profibrillin-1 immunoprecipitation studies revealed that two endoplasmic reticulum-resident molecular chaperones, BiP and GRP94, interacted with profibrillin-1. To determine the proprotein convertase responsible for processing profibrillin-1, a specific inhibitor of furin, α-1-antitrypsin, Portland variant, was both expressed in the cells and added to cells exogenously. In both cases, the inhibitor blocked the processing of profibrillin-1, providing evidence that furin is the enzyme responsible for profibrillin-1 processing. These studies delineate the secretion and proteolytic processing of profibrillin-1, and identify the proteins that interact with profibrillin-1 in the secretory pathway.

Original languageEnglish
Pages (from-to)641-652
Number of pages12
JournalJournal of Cellular Biochemistry
Volume90
Issue number3
DOIs
StatePublished - Oct 15 2003

Keywords

  • Chaperones
  • Extracellular matrix
  • Fibrillin-1
  • Furin
  • Processing

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