« TANGO1 builds a secretory route for collagen »

Secreted collagens compose 20% of our dry body weight and are necessary for tissue formation. Dysregulated collagen secretion affects every organ system and is the pathophysiological hallmark of a broad range of diseases encompassing collagenopathies and fibrosis. Modulation of excessive collagen deposition, could therefore offer an effective disease-modifying therapeutic approach. One solution to this problem comes from our studies of how these bulky cargoes are exported from the endoplasmic reticulum (ER), despite being too big to fit into a conventional COPII vesicle. Our discovery of TANGO1 has made the pathway of bulky cargo secretion amenable to molecular analysis and therapeutic control. TANGO1 connects collagen in the ER lumen to cytoplasmic membrane-sculpting machinery, including COPII coat components. A TANGO1 filament surrounds, corrals, and scaffolds COPII coat assembly at an ER exit site (ERES). It recruits a multisubunit tethering complex to link ER export to retrograde COPI-coated ERGIC membranes. Altogether, TANGO1 stabilizes a transient tunnel for bulky secretory cargo export without involving a bona fide vesicular intermediate as per Palade’s classical model of protein transport. We developed membrane-permeant peptide inhibitors of TANGO1. We show that the peptides act as competitive inhibitors of TANGO1 function, which allowed us to control collagen secretion in cells, primary tissue derived from patients with scleroderma, and in vivo, including in a murine model of skin fibrosis. Our results show that acute control of TANGO1 could provide a disease-modifying therapy for such collagenopathies.