TANGO1 inhibitors reduce collagen secretion and limit tissue scarring

Ishier Raote (), Ann-Helen Rosendahl, Hanna-Maria Häkkinen, Carina Vibe, Ismail Küçükaylak, Mugdha Sawant, Lena Keufgens, Pia Frommelt, Kai Halwas, Katrina Broadbent, Marina Cunquero, Gustavo Castro, Marie Villemeur, Julian Nüchel, Anna Bornikoel, Binita Dam, Ravindra K. Zirmire, Ravi Kiran, Carlo Carolis, Jordi Andilla, Pablo Loza-Alvarez, Verena Ruprecht, Colin Jamora, Felix Campelo, Marcus Krüger, Matthias Hammerschmidt, Beate Eckes, Ines Neundorf (), Thomas Krieg and Vivek Malhotra ()
Additional contact information
Ishier Raote: The Barcelona Institute of Science and Technology
Ann-Helen Rosendahl: Medical Faculty
Hanna-Maria Häkkinen: The Barcelona Institute of Science and Technology
Carina Vibe: The Barcelona Institute of Science and Technology
Ismail Küçükaylak: University of Cologne
Mugdha Sawant: Medical Faculty
Lena Keufgens: University of Cologne
Pia Frommelt: University of Cologne
Kai Halwas: University of Cologne
Katrina Broadbent: The Barcelona Institute of Science and Technology
Marina Cunquero: The Barcelona Institute of Science and Technology
Gustavo Castro: The Barcelona Institute of Science and Technology
Marie Villemeur: Institut Jacques Monod
Julian Nüchel: Max Planck Institute for Biology of Aging
Anna Bornikoel: Medical Faculty
Binita Dam: Institute for Stem Cell Science and Regenerative Medicine (inStem)
Ravindra K. Zirmire: Institute for Stem Cell Science and Regenerative Medicine (inStem)
Ravi Kiran: Institute for Stem Cell Science and Regenerative Medicine (inStem)
Carlo Carolis: The Barcelona Institute of Science and Technology
Jordi Andilla: The Barcelona Institute of Science and Technology
Pablo Loza-Alvarez: The Barcelona Institute of Science and Technology
Verena Ruprecht: The Barcelona Institute of Science and Technology
Colin Jamora: Institute for Stem Cell Science and Regenerative Medicine (inStem)
Felix Campelo: The Barcelona Institute of Science and Technology
Marcus Krüger: University of Cologne
Matthias Hammerschmidt: University of Cologne
Beate Eckes: Medical Faculty
Ines Neundorf: University of Cologne
Thomas Krieg: Medical Faculty
Vivek Malhotra: The Barcelona Institute of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring and fibrosis and compromise tissue function. Despite the widespread occurrence of fibrotic diseases and scarring, effective therapies are lacking. A promising approach would be to limit the amount of collagen released from hyperactive fibroblasts. We have designed membrane permeant peptide inhibitors that specifically target the primary interface between TANGO1 and cTAGE5, an interaction that is required for collagen export from endoplasmic reticulum exit sites (ERES). Application of the peptide inhibitors leads to reduced TANGO1 and cTAGE5 protein levels and a corresponding inhibition in the secretion of several ECM components, including collagens. Peptide inhibitor treatment in zebrafish results in altered tissue architecture and reduced granulation tissue formation during cutaneous wound healing. The inhibitors reduce secretion of several ECM proteins, including collagens, fibrillin and fibronectin in human dermal fibroblasts and in cells obtained from patients with a generalized fibrotic disease (scleroderma). Taken together, targeted interference of the TANGO1-cTAGE5 binding interface could enable therapeutic modulation of ERES function in ECM hypersecretion, during wound healing and fibrotic processes.

Date: 2024
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DOI: 10.1038/s41467-024-47004-1

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