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

Nüchel, Julian; Ghatak, Sushmita; Zuk, Alexandra V.; Illerhaus, Anja; Mörgelin, Matthias LU ; Schönborn, Katrin; Blumbach, Katrin; Wickström, Sara A.; Krieg, Thomas and Sengle, Gerhard, et al. (2018) In Autophagy 14(3). p.465-486
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,... (More)

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.

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published
subject
keywords
ARHGAP26/GRAF1, fibrosis, GORASP2/GRASP55, ILK, LIR motif, LTBP1, RAB8, RHOA, secretory autophagy, TNF
in
Autophagy
volume
14
issue
3
pages
465 - 486
publisher
Landes Bioscience
external identifiers
  • scopus:85044051124
ISSN
1554-8627
DOI
10.1080/15548627.2017.1422850
language
English
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yes
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6b3cb43f-2cff-437b-b2cd-3a8382892d85
date added to LUP
2018-04-05 14:21:11
date last changed
2019-09-17 04:29:14
@article{6b3cb43f-2cff-437b-b2cd-3a8382892d85,
  abstract     = {<p>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.</p>},
  author       = {Nüchel, Julian and Ghatak, Sushmita and Zuk, Alexandra V. and Illerhaus, Anja and Mörgelin, Matthias and Schönborn, Katrin and Blumbach, Katrin and Wickström, Sara A. and Krieg, Thomas and Sengle, Gerhard and Plomann, Markus and Eckes, Beate},
  issn         = {1554-8627},
  keyword      = {ARHGAP26/GRAF1,fibrosis,GORASP2/GRASP55,ILK,LIR motif,LTBP1,RAB8,RHOA,secretory autophagy,TNF},
  language     = {eng},
  month        = {03},
  number       = {3},
  pages        = {465--486},
  publisher    = {Landes Bioscience},
  series       = {Autophagy},
  title        = {TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators},
  url          = {http://dx.doi.org/10.1080/15548627.2017.1422850},
  volume       = {14},
  year         = {2018},
}