TUG protein acts through a disordered region to organize the early secretory pathway

The endoplasmic reticulum (ER)-Golgi Intermediate Compartment (ERGIC) is a distinct compartment in mammalian cells, which forms in part by homotypic fusion of ER-derived vesicles and gives rise to the cis cisterna of the Golgi ribbon. How the ERGIC is regulated is not well understood. Here we show that the TUG protein is essential to maintain this compartment as a distinct organelle. TUG (UBXN9, Aspscr1) is known to regulate the cell type -specific trafficking of GLUT4 glucose transporters, but its role in more ubiquitous trafficking pathways has not been well characterized. TUG localized to the ERGIC and in fibroblasts its deletion enhanced anterograde flux and increased resorption of ERGIC markers into the cis-Golgi, perturbing membrane homeostasis in the early secretory pathway. TUG knockout cells had a compacted Golgi morphology, and ultrastructural studies revealed dilated cisterna with surrounding small vesicles. A central disordered region in TUG mediated its recruitment to ERGIC membranes, and an amino terminal domain was sufficient to induce oligomerization in cells. In TUG knockout cells, ERGIC-dependent processes such as autophagy are disrupted and model cargoes such as CFTR are missorted. Together, these results reveal a novel, TUG-dependent regulatory mechanism in the early secretory pathway, which modulates ERGIC organization and anterograde trafficking. This function is co-opted by GLUT4 and other proteins that employ an unconventional secretion pathway to the plasma membrane.