A New Pathway for Collagen Secretion and Wound Healing Control

Receptor-mediated trafficking of secretory cargo at endoplasmic reticulum (ER) via small COPII vesicles is well understood, but the secretion of large cargoes like collagens, mucins, lipoproteins, and antibodies presents challenges due to their size, quantities secreted, and lack of specific receptors. Our discovery of TANGO1, along with cTAGE5 and TANGO1-short, unveils a unique mechanism in which TANGO1 functions to tunnel collagens from ER to the next secretory compartments, bypassing vesicular intermediates. We identified two types of TANGO1 mutations: Class 1 mutations lead to gene deletion and fetal demise, while Class 2 mutations produce a spliced variant that impairs collagen export. Patients with these mutations show short stature, skeletal and dermal abnormalities, and intellectual disability. We also identified two distinct ER exit portals: bulky collagens are confined to about 40% of these sites, while smaller cargoes can exit through any available gate. Our work demonstrates that targeting TANGO1 with membrane-permeant inhibitors controls hypercollagen secretion in dermal cells from scleroderma patients and in a zebrafish wound healing model. These findings present new therapeutic avenues for collagen-related disorders, which will be discussed.