Universität zu Köln

Nuechel, Julian, Ghatak, Sushmita, Zuk, Alexandra V., Illerhaus, Anja, Morgelin, Matthias, Schoenborn, Katrin, Blumbach, Katrin, Wickstroem, Sara A., Krieg, Thomas, Sengle, Gerhard, Plomann, Markus and Eckes, Beate (2018). TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators. Autophagy, 14 (3). S. 465 - 487. PHILADELPHIA: TAYLOR & FRANCIS INC. ISSN 1554-8635

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nuechel, Julian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ghatak, Sushmita UNSPECIFIED UNSPECIFIED UNSPECIFIED Zuk, Alexandra V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Illerhaus, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Morgelin, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoenborn, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Blumbach, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Wickstroem, Sara A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krieg, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Plomann, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Eckes, Beate UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-200091
DOI:	10.1080/15548627.2017.1422850
Journal or Publication Title:	Autophagy
Volume:	14
Number:	3
Page Range:	S. 465 - 487
Date:	2018
Publisher:	TAYLOR & FRANCIS INC
Place of Publication:	PHILADELPHIA
ISSN:	1554-8635
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR-BETA; INTEGRIN-LINKED KINASE; EXTRACELLULAR-MATRIX; BINDING-PROTEINS; LATENT TGF-BETA-1; SYSTEMIC-SCLEROSIS; GRANULATION-TISSUE; FACTOR-ALPHA; ACTIVATION; CELLS Multiple languages Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/20009