Abstract
Dysregulation of collagen production and secretion contributes to aging and tissue fibrosis of major organs. How procollagen proteins in the endoplasmic reticulum (ER) route as specialized cargos for secretion remains to be fully elucidated. Here, we report that TMEM39, an ER-localized transmembrane protein, regulates production and secretory cargo trafficking of procollagen. We identify the C. elegans ortholog TMEM-39 from an unbiased RNAi screen and show that deficiency of tmem-39 leads to striking defects in cuticle collagen production and constitutively high ER stress response. RNAi knockdown of the tmem-39 ortholog in Drosophila causes similar defects in collagen secretion from fat body cells. The cytosolic domain of human TMEM39A binds to Sec23A, a vesicle coat protein that drives collagen secretion and vesicular trafficking. TMEM-39 regulation of collagen secretion is independent of ER stress response and autophagy. We propose that the roles of TMEM-39 in collagen secretion and ER homeostasis are likely evolutionarily conserved.
Highlights
Collagen is the major molecular component of connective tissues, and the most abundant protein in animals [1]
Human TMEM39A directly interacts with SEC23A, a core component of the complex II (COPII) vesicle coating complex responsible for vesicular cargo secretion to the Golgi apparatus
We identified D1007.5, the sole tmem-39 homolog in C. elegans, from a genome-wide RNAi screen for genes affecting the abundance of transgenic reporter asp-17p::GFP, which is up-regulated by temperature stress and down-regulated by endoplasmic reticulum (ER) stress [25]
Summary
Collagen is the major molecular component of connective tissues, and the most abundant protein in animals [1]. Specialized intracellular vesicles defined by the coat protein complex II (COPII) transport most secreted proteins, including procollagen, from the ER to the Golgi apparatus [9,10]. Large-size COPII-coated vesicles may transport procollagen from the ER to the Golgi apparatus. TANGO1, a transmembrane protein at the ER exit site, mediates formation of specialized collagen-transporting vesicle and recruitment of procollagen [14,15,16]. The N-terminal SH3-like domain of TANGO1 binds to the collagen chaperone HSP47 in the ER lumen, recruiting procollagens to the ER exit site [17]. The coilcoil domain of TANGO1 forms a stable complex with cTAE5 and SEC12, which is enriched around large COPII carriers for procollagen [19]. TANGO1 organizes ER exit sites by creating a lipid diffusion barrier and an export conduit for collagen [20]
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