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

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 transport ^1–5 . Vitellogenin forms part of yolk granules (also known as yolk organelles), as maternal contribution of nutrients that support the embryonic development of oviparous animals ^6,7 . In Caenorhabditis elegans , vitellogenin proteins (VIT-1 to VIT-6) are synthesized in the hermaphrodite intestine, secreted into the pseudocoelom and internalized by oocytes ^8–13 . Although a general route for inter-tissue vitellogenin transport has been described, the full mechanism that underlies its intracellular trafficking within the intestine remains obscure ^9,12,13 . 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 sites ^14–17 . Transport facilitated by TANGO1 family of proteins is considered as an alternative, COPII-independent ER exit pathway ^18–24 . Thus far, TANGO1 orthologs have been discovered in most metazoans, except nematodes ^24,25 . Here, we report the C. elegans protein R148.3 (now T ra n sport and G olgi organization 1- l ike 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.