PUBLICATION
TANGO1 inhibitors reduce collagen secretion and limit tissue scarring
- Authors
- Raote, I., Rosendahl, A.H., Häkkinen, H.M., Vibe, C., Küçükaylak, I., Sawant, M., Keufgens, L., Frommelt, P., Halwas, K., Broadbent, K., Cunquero, M., Castro, G., Villemeur, M., Nüchel, J., Bornikoel, A., Dam, B., Zirmire, R.K., Kiran, R., Carolis, C., Andilla, J., Loza-Alvarez, P., Ruprecht, V., Jamora, C., Campelo, F., Krüger, M., Hammerschmidt, M., Eckes, B., Neundorf, I., Krieg, T., Malhotra, V.
- ID
- ZDB-PUB-240425-14
- Date
- 2024
- Source
- Nature communications 15: 33023302 (Journal)
- Registered Authors
- Hammerschmidt, Matthias, Loza-Alvarez, Pablo
- Keywords
- none
- MeSH Terms
-
- Animals
- Cicatrix*/drug therapy
- Cicatrix*/metabolism
- Cicatrix*/pathology
- Collagen*/metabolism
- Endoplasmic Reticulum/drug effects
- Endoplasmic Reticulum/metabolism
- Extracellular Matrix/drug effects
- Extracellular Matrix/metabolism
- Fibroblasts*/drug effects
- Fibroblasts*/metabolism
- Fibrosis
- Humans
- Peptides/metabolism
- Peptides/pharmacology
- Scleroderma, Systemic/drug therapy
- Scleroderma, Systemic/metabolism
- Scleroderma, Systemic/pathology
- Skin/drug effects
- Skin/metabolism
- Skin/pathology
- Wound Healing*/drug effects
- Zebrafish*
- PubMed
- 38658535 Full text @ Nat. Commun.
Citation
Raote, I., Rosendahl, A.H., Häkkinen, H.M., Vibe, C., Küçükaylak, I., Sawant, M., Keufgens, L., Frommelt, P., Halwas, K., Broadbent, K., Cunquero, M., Castro, G., Villemeur, M., Nüchel, J., Bornikoel, A., Dam, B., Zirmire, R.K., Kiran, R., Carolis, C., Andilla, J., Loza-Alvarez, P., Ruprecht, V., Jamora, C., Campelo, F., Krüger, M., Hammerschmidt, M., Eckes, B., Neundorf, I., Krieg, T., Malhotra, V. (2024) TANGO1 inhibitors reduce collagen secretion and limit tissue scarring. Nature communications. 15:33023302.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping