Stress-induced secretory pathway disruption causes atypical metalloproteinase transport in PMM2-CDG.

Matrix metalloproteinase (Mmp) dysfunction has been implicated as a driver of cartilage and neuromuscular pathologies in a common congenital disorder of glycosylation, PMM2-CDG. Since Mmp activity and interactions can be regulated by their glycans, these abnormalities were thought to likely arise from direct effects on enzyme glycosylation. However, here we show that disruptions in secretory pathway morphology alter the trafficking of Mmp2 and its activator, membrane-type Mmp MT1-Mmp. Biochemical and visual studies indicate enhanced processing by a furin proconvertase causes MT1-Mmp to directly exit the ER, bypassing the Golgi. This unconventional route of cell surface transport prevents MT1-Mmp and Mmp2 from interacting inside chondrocytes, causing pro-Mmp2 to accumulate in the Golgi. Importantly, defects in Mmp trafficking do not appear to correspond to direct defects in the N-glycosylation of either enzyme, suggesting that stress-induced alterations in secretory pathway organization may instead underlie the atypical Mmp trafficking in PMM2-CDG.