Targeting Collagen Secretion as a Potential Therapeutic Strategy to Modulate Fibrosis

Abstract

Fibrotic diseases are driven by the excessive accumulation of extracellular matrix (ECM), particularly collagens, leading to progressive tissue stiffness and organ dysfunction. While many factors contribute to fibrosis—including cytokine signaling, integrin-mediated mechanotransduction, and altered ECM degradation—the synthesis and secretion of collagen remain central bottlenecks. Collagen biosynthesis is a complex process involving extensive post-translational modification and intracellular trafficking. The export of procollagen from the endoplasmic reticulum (ER) requires Transport and Golgi Organisation 1 (TANGO1), a transmembrane organizer of ER exit sites that coordinates cargo selection, membrane remodeling, and connectivity between the ER and the ER-Golgi-Intermediate-Comaprtment (ERGIC). By assembling into ring-like structures at ER exit sites, TANGO1 builds a secretory route for bulky cargoes that bypasses conventional vesicle constraints. Loss of TANGO1 disrupts collagen secretion and causes developmental defects across various species. In fibrotic tissues, TANGO1 expression is upregulated, linking secretory machinery to pathological matrix deposition. Recent work has identified specific interfaces within the complex of TANGO1 with its vertebrate paralogue Cutaneous T-cell lymphoma-associated antigen 5 (cTAGE5) as targets for cell-permeant peptide inhibitors. Inhibitors that selectively and specifically block TANGO1 complex formation reduce collagen secretion in fibroblasts and scar formation in vivo, offering a new strategy to modulate fibrotic processes.

Keywords

TANGO1 / Extracellular matrix / Scleroderma / Large cargo / Endoplasmic reticulum / Peptide

Acknowledgements

The authors thank Vivek Malhotra (CRG Barcelona) for continued stimulating discussion.

Author Contributions

Conceptualization, B.E., G.S., I.R., T.K.; Writing—original draft preparation, B.E., G.S., I.R., T.K.; Writing—review and editing, O.T, A.B., J.N., I.N., G.S., B.E., I.R., T.K.; Visualization, O.T.; Funding acquisition, I.R., J.N., G.S., T.K.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Funding

Parts of this work were supported by Deutsche Forschungsgemeinschaft (German Research Foundation) through KR 558/17 and SE 115/7-1 (project ID 468236352 to T.K. and G.S.) and through the Research Unit Grant FOR2722 (NU 467/1-1 and DE 3170/1-1; project ID 384170921 to J.N.). JN acknowledges support by the Center for Molecular Medicine Cologne (CMMC) through the Individual Project Funding Program (Project C10) and the Career Advancement Program (Project CAP31) (to J.N.). T.K. is supported by CECAD and CMMC (SRG). I.R. acknowledges the support of Fondation pour la Recherche Médicale (grant AJE202210016216) and the ANR (MatSec).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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