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

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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.