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

Chia-Lun Wu1,2, Kali Wiggins1, Lynn Dukes-Rimsky1

  • 1JC Self Research Institute, Greenwood Genetic Center, Greenwood, SC 29646, USA.

Iscience
|August 20, 2026
PubMed

Insights

Matrix metalloproteinase (Mmp) dysfunction in PMM2-CDG is driven by altered secretory pathway morphology, not direct glycosylation defects. This leads to abnormal Mmp trafficking, impacting cartilage and neuromuscular health.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Genetics

Background:

  • Matrix metalloproteinase (Mmp) dysfunction contributes to cartilage and neuromuscular pathologies in PMM2-CDG.
  • Mmp activity is regulated by glycans, suggesting direct glycosylation defects in PMM2-CDG.

Purpose of the Study:

  • To investigate the mechanisms underlying Mmp dysfunction in PMM2-CDG.
  • To determine if Mmp abnormalities arise from direct glycosylation defects or altered trafficking.

Main Methods:

  • Biochemical assays to analyze Mmp processing and localization.
  • Visual studies using microscopy to examine secretory pathway morphology and protein trafficking.

Main Results:

  • Disruptions in secretory pathway morphology alter Mmp2 and MT1-Mmp trafficking.
  • Enhanced furin proconvertase processing causes MT1-Mmp to bypass the Golgi, preventing Mmp interaction within chondrocytes.
  • Pro-Mmp2 accumulates in the Golgi due to impaired Mmp trafficking.

Conclusions:

  • Atypical Mmp trafficking in PMM2-CDG is linked to stress-induced alterations in secretory pathway organization.
  • The findings suggest that Mmp dysfunction in PMM2-CDG is primarily a trafficking defect, not a direct glycosylation issue.
Keywords:
CDGMMPglycosylationsecretory pathwayunconventional trafficking

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