The conserved ER-transmembrane protein TMEM39 coordinates with COPII to promote collagen secretion and prevent ER stress

Abstract

Dysregulation of collagen production and secretion contributes to aging and tissue fibrosis of major organs. How premature collagen proteins in the endoplasmic reticulum (ER) route in specialized vesicles 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 orthologue 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 orthologue in Drosophila causes similar defects in collagen secretion in fat body cells. The cytosolic domain of the human orthologue TMEM39A binds to Sec23A, a vesicle coat protein that drives collagen secretion and vesicular trafficking. We propose that roles of TMEM39 in collagen secretion and preventing ER stress are likely evolutionarily conserved.

A general role for MIA3/TANGO1 in secretory pathway organization and function

“…This work is also more consistent with a general role for TANGO1 in organization of ERES. Notably C. elegans do not express TANGO1 but TMEM131 (Zhang et al, 2020) and/or TMEM39 (Zhang et al, 2021) might play a similar role in collagen secretion in nematodes. Overall, our data support models where ECM proteins are the cohort of secretory cargo most sensitive to perturbation of early secretory pathway function.…”

Downregulation of TMEM220 Promotes Tumor Progression in Hepatocellular Carcinoma

“…Mechanism studies showed that overexpression of TMEM220 could regulate β-catenin and FOXO3 transcriptional activity by altering their subcellular localization, affecting the expression of downstream gene p21 and SNAIL, and ultimately reducing the progression of HCC.Conclusion: Altogether, our study proposes a working model in which upregulation of TMEM220 expression alters the genes expression involved in cell proliferation, thereby inhibiting HCC progression, which suggests that TMEM220 might serve as a clinical biomarker.Transmembrane protein 220 (TMEM220) is a family member of TMEMs that spans the entire width of the lipid bilayer and is permanently anchored. Many TMEMs from mammalian cells are well characterized in term of biological functions and structures [15][16][17][18], like G protein-coupled receptors (GPCR) [19][20][21], while the subcellular localization, physiological function and its role in cancer of TMEM220 remain blank. Recent studies reported LncRNAs TMEM220 is associated with HCC patients survival, and TMEM220 gene expression is downregulated in gastric cancer [22,23].…”

“…Transmembrane protein 220 (TMEM220) is a family member of TMEMs that spans the entire width of the lipid bilayer and is permanently anchored. Many TMEMs from mammalian cells are well characterized in term of biological functions and structures [15][16][17][18], like G protein-coupled receptors (GPCR) [19][20][21], while the subcellular localization, physiological function and its role in cancer of TMEM220 remain blank. Recent studies reported LncRNAs TMEM220 is associated with HCC patients survival, and TMEM220 gene expression is downregulated in gastric cancer [22,23].…”