Abnormal Trafficking and Processing of Multiple Matrix Metalloproteinases Drive Cartilage Defects in Congenital Disorders of Glycosylation

Author

• Chia-Lun WuFollow

Date of Award

5-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Genetics and Biochemistry

Committee Chair/Advisor

Dr. Trudy Frances Charlene Mackay

Committee Member

Dr. Heather Flanagan-Steet

Committee Member

Dr. Richard Steet

Committee Member

Dr. Kerry Smith

Committee Member

Dr. Andrei Alexandrov

Abstract

Congenital Disorders of Glycosylation (CDG) are rare metabolic diseases caused by defects in glycosylation. Despite identification of over 200 CDG types, the mechanisms linking glycosylation defects to diverse clinical phenotypes remain unclear. This dissertation uses zebrafish models of PMM2-CDG and STT3-CDG to redefine CDG pathogenesis, shifting from a simple glycan deficiency model to one involving disrupted cellular spatial organization.

We identify a protease-dependent pathway underlying craniofacial cartilage defects. Specifically, defective proteolytic processing of N-cadherin, a key adhesion molecule in chondrogenesis, is a central driver of pathology. We further uncover an unconventional trafficking mechanism in which ER stress and altered secretory pathway architecture reroute MT1-MMP (MMP14) directly from the ER to the plasma membrane, bypassing the Golgi. In contrast, its activator MMP2 is retained in fragmented, Giantin-positive Golgi compartments, preventing enzyme interaction and leaving MMP2 inactive. This spatial uncoupling disrupts coordinated proteolysis, impairing N-cadherin maturation and leading to cartilage defects.

In PMM2 mutants, mislocalization of furin to the ER may contribute to premature MT1-MMP activation. In STT3-CDG, loss of STT3A or STT3B destabilizes the oligosaccharyltransferase (OST) complex, triggering unfolded protein response activation and phenotypes similar to PMM2-CDG.

Finally, epalrestat reduces metabolic stress, stabilizes secretory pathway organization, and rescues cartilage structure. Together, these findings redefine CDG as a multifactorial disorder driven by glycosylation defects, protease misregulation, secretory pathway disorganization, and metabolic stress, highlighting organelle homeostasis as a therapeutic target.

Recommended Citation

Wu, Chia-Lun, "Abnormal Trafficking and Processing of Multiple Matrix Metalloproteinases Drive Cartilage Defects in Congenital Disorders of Glycosylation" (2026). All Dissertations. 4245.
https://open.clemson.edu/all_dissertations/4245