Journal Article

TANGO1 inhibitors reduce collagen secretion and limit tissue scarring

Zirmire, Ravindra K., Kiran, Ravi, Krüger, Marcus, Neundorf, Ines, Vibe, Carina, Eckes, Beate, Sawant, Mugdha, Castro, Gustavo, Halwas, Kai, Küçükaylak, Ismail, Loza-Alvarez, Pablo, Raote, Ishier, Bornikoel, Anna, Carolis, Carlo, Keufgens, Lena, Rosendahl, Ann-Helen, Andilla, Jordi, Malhotra, Vivek, Broadbent, Katrina, Nüchel, Julian, Frommelt, Pia, Jamora, Colin, Krieg, Thomas, Villemeur, Marie, Campelo, Felix, Hammerschmidt, Matthias, Ruprecht, Verena, Häkkinen, Hanna-Maria, Cunquero, Marina, Dam, Binita

2024

Overview

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. Uncontrolled secretion of ECM proteins, such as collagen, can lead to excessive scarring. Here the authors describe membrane permeable peptides that target the interface of TANGO1 and cTAGE5, inhibit secretion of ECM components and could be of therapeutic benefit during wound healing and fibrotic processes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/51 / 14/19 / 14/63 / 631/80/304 / 631/80/313/1463 / 64/116 / 82/1 / 82/58 / 82/80 / Animals / Cicatrix - drug therapy / Cicatrix - metabolism / Cicatrix - pathology / Collagen / Collagen - metabolism / Endoplasmic reticulum / Endoplasmic Reticulum - drug effects / Endoplasmic Reticulum - metabolism / Extracellular matrix / Extracellular Matrix - drug effects / Extracellular Matrix - metabolism / Fibrillin / Fibroblasts / Fibroblasts - drug effects / Fibroblasts - metabolism / Fibronectin / Fibrosis / Granulation / Humanities and Social Sciences / Humans / Inhibitors / Life Sciences / Membranes / multidisciplinary / Peptide inhibitors / Peptides / Peptides - metabolism / Peptides - pharmacology / Proteins / Science / Science (multidisciplinary) / Scleroderma / Scleroderma, Systemic - drug therapy / Scleroderma, Systemic - metabolism / Scleroderma, Systemic - pathology / Secretion / Skin - drug effects / Skin - metabolism / Skin - pathology / Wound healing / Wound Healing - drug effects / Zebrafish