• Home
  • Search Results
  • TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators.

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

Autophagy (2018-01-04)
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

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.

Product Number
Product Description

TWEEN® 20, for molecular biology, viscous liquid
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
DAPI, for nucleic acid staining
IGEPAL® CA-630, for molecular biology
PMA, for use in molecular biology applications, ≥99% (HPLC)
Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
3-Methyladenine, autophagy inhibitor
Anti-LC3B antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution
Anti-HA-Biotin, High Affinity (3F10), from rat IgG1
4-Hydroxytamoxifen, analytical standard, (E) and (Z) isomers (50:50)
Mechlorethamine hydrochloride, 98%
Anti-GAPDH Antibody, from rabbit, purified by affinity chromatography
Anti-ATG5 (N-terminal) antibody produced in rabbit, affinity isolated antibody, PBS solution
Anti-RAB8A antibody produced in goat, affinity isolated antibody, buffered aqueous solution