TMEM39A and TMEM131 facilitate bulk transport of ECM proteins through large COPII vesicle formation.

The growth of Caenorhabditis elegans involves multiple molting processes, during which old cuticles are shed and new cuticles are rapidly formed. This process requires the regulated bulk secretion of cuticle components. The transmembrane protein-39 (TMEM-39) mutant exhibits distinct dumpy and ruptured phenotypes characterized by notably thin cuticles. TMEM-39 primarily co-localizes with the coat protein II complex (COPII) in large vesicles rather than small COPII vesicles. These TMEM-39-associated large vesicles (TMEM-39-LVs) form robustly during the molting period and co-localize with various extracellular matrix (ECM) components, including BLI-1 collagen, BLI-3 dual oxidase, and carboxypeptidases. Through immunoprecipitation using TMEM39A-FLAG and proteomics analysis in human sarcoma cells, we identify TMEM39A-associated proteins, including TMEM131. Knockdown of TMEM131 results in reduced TMEM39A-LV formation and collagen secretion in both C. elegans and human sarcoma cells, indicating a cooperative role between TMEM39A and TMEM131 in the secretion of extracellular components through the formation of large COPII vesicles. Given the conservation of TMEM39A and its associated proteins between C. elegans and humans, TMEM39A-LV may represent a fundamental machinery for rapid and extensive secretion across metazoans.