TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators

Research output: Contribution to journalArticle

Abstract

TGFB1 (transforming growth factor beta 1) is a potent cytokine playing a driving role in development, fibrosis and cancer. It is synthesized as prodomain-growth factor complex that requires tethering to LTBP (latent transforming growth factor beta binding protein) for efficient secretion into the extracellular space. Upon release, this large latent complex is sequestered by anchorage to extracellular matrix (ECM) networks, from which the mature growth factor needs to be activated in order to reach its receptors and initiate signaling. Here, we uncovered a novel intracellular secretion pathway by which the latent TGFB1 complex reaches the plasma membrane and is released from fibroblasts, the key effector cells during tissue repair, fibrosis and in the tumor stroma. We show that secretion of latent TGFB1, but not of other selected cytokines or of bulk cargo, is regulated by fibroblast-ECM communication through ILK (integrin linked kinase) that restricts RHOA activity by interacting with ARHGAP26/GRAF1. Latent TGFB1 interacts with GORASP2/GRASP55 and is detected inside MAP1LC3-positive autophagosomal intermediates that are secreted by a RAB8A-dependent pathway. Interestingly, TGFB1 secretion is fully abrogated in human and murine fibroblasts and macrophages that lack key components of the autophagic machinery. Our data demonstrate an unconventional secretion mode of TGFB1 adding another level of control of its bioavailability and activity in order to effectively orchestrate cellular programs prone to dysregulation as seen in fibrosis and cancer.

Details

Authors
  • Julian Nüchel
  • Sushmita Ghatak
  • Alexandra V. Zuk
  • Anja Illerhaus
  • Matthias Mörgelin
  • Katrin Schönborn
  • Katrin Blumbach
  • Sara A. Wickström
  • Thomas Krieg
  • Gerhard Sengle
  • Markus Plomann
  • Beate Eckes
Organisations
External organisations
  • University of Cologne
  • Max Planck Institute for Biology of Ageing
  • Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • ARHGAP26/GRAF1, fibrosis, GORASP2/GRASP55, ILK, LIR motif, LTBP1, RAB8, RHOA, secretory autophagy, TNF
Original languageEnglish
Pages (from-to)465-486
JournalAutophagy
Volume14
Issue number3
Early online date2018 Mar 1
Publication statusPublished - 2018 Mar 4
Publication categoryResearch
Peer-reviewedYes