TANGO1 inhibitors reduce collagen secretion and limit tissue scarring

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  • dc.contributor.author Raote, Ishier
  • dc.contributor.author Häkkinen, Hanna-Maria
  • dc.contributor.author Vibe, Carine
  • dc.contributor.author Broadbent, Katrina
  • dc.contributor.author Carolis, Carlo
  • dc.contributor.author Ruprecht, Verena
  • dc.contributor.author Malhotra, Vivek
  • dc.date.accessioned 2024-09-06T06:14:24Z
  • dc.date.available 2024-09-06T06:14:24Z
  • dc.date.issued 2024
  • dc.description.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.
  • dc.description.sponsorship The authors thank the CRG Advanced Light Microscopy Unit (ALMU), the Protein Technologies Unit, and the CRG/UPF Flow Cytometry Unit. Susanne Neumann (Cologne) provided excellent technical assistance. We would like to thank Prof. Dr. Pia Moinzadeh for obtaining the skin biopsies. The authors acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Catalunya and the Alexander v. Humboldt foundation. We acknowledge financial support from the following sources: Ministerio de Economía y Competitividad (SEV-2012-0208, BFU2013-44188-P, CSD2009-00016 to V.M.); Deutsche Forschungsgemeinschaft (ID 468236352) and CMMC Cologne to T.K and V.M. V.R. acknowledges financial support from the Ministerio de Ciencia y Innovacion through the Plan Nacional (PID2020-117011GB-I00). This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No 951146). This publication is part of the Project TARTAFI (Ref. PDC2021-121870-I00), funded by MCIN/AEI/10.13039/501100011033 and the European Union “NextGenerationEU”/PRTR. This work was supported by the Fondation pour la Recherche Médicale, (FRM) AJE202210016216 to I.R. M.C, G.C, F.C, J.A, and PL-A acknowledge funding from Fundació CELLEX; Ministerio de Economıa y Competitividad - Severo Ochoa programme for Centres of Excellence in R&D (CEX2019-000910-S); CERCA programme and Laserlab-Europe (871124); Ministerio de Ciencia e Innovación (MCIN/AEI/10.13039/501100011033); and Fondo Social Europeo (PRE2020-095721, M.C). The SLN facility corresponds to a “Grup reconegut 2021 SGR 01456 pel Departament de Recerca i Universitats de la Generalitat de Catalunya”. F.C. acknowledges support from the Government of Spain (RYC-2017–22227, PID2019-106232RB-I00/10.13039/501100011033/110198RB-I00).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Raote I, Rosendahl AH, Häkkinen HM, Vibe C, Küçükaylak I, Sawant M, et al. TANGO1 inhibitors reduce collagen secretion and limit tissue scarring. Nat Commun. 2024 Apr 24;15(1):3302. DOI: 10.1038/s41467-024-47004-1
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-024-47004-1
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/61031
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2024 Apr 24;15(1):3302
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/951146
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SEV-2012-0208
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-44188-P
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/CSD2009-00016
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-117011GB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PDC2021-121870-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/CEX2019-000910-S
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/871124
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PRE2020-095721
  • dc.rights © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Endoplasmic reticulum
  • dc.subject.keyword Mechanisms of disease
  • dc.title TANGO1 inhibitors reduce collagen secretion and limit tissue scarring
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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