A distant TANGO1 family member promotes vitellogenin export from the ER in C. elegans

Abstract

Vitellogenin belongs to the Large Lipid Transfer Protein superfamily and is thought to share a common ancestor with human Apolipoprotein B (ApoB) for systemic lipid transport1-5. Vitellogenin forms part of yolk granules (also known as yolk organelles), as maternal contribution of nutrients that support the embryonic development of oviparous animals6,7. In Caenorhabditis elegans, vitellogenin proteins (VIT-1 to VIT-6) are synthesized in the hermaphrodite intestine, secreted into the pseudocoelom and internalized by oocytes8-13. Although a general route for inter-tissue vitellogenin transport has been described, the full mechanism that underlies its intracellular trafficking within the intestine remains obscure9,12,13. In humans, transport and Golgi organization protein 1 (TANGO1) and TANGO1-like (TALI) proteins generate super-sized membrane carriers to accommodate bulky ApoB-containing lipoprotein particles for their export from ER exit sites14-17. Transport facilitated by TANGO1 family of proteins is considered as an alternative, COPII-independent ER exit pathway18-24. Thus far, TANGO1 orthologs have been discovered in most metazoans, except nematodes24,25. Here, we report the C. elegans protein R148.3 (now Transport and Golgi organization 1-like or TNGL-1) as a mediator of vitellogenin export from the ER. TNGL-1 depletion triggers VIT-2 accumulation in the intestinal ER lumen. TNGL-1 requires its C-terminal unstructured domain for its localization to ER exit sites. Like TANGO1, it utilizes a luminal globular domain for cargo engagement. Our findings support TNGL-1 as a distant TANGO1 family member.