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Authors: Fridrich, Sven
Hahn, Susanne A.
Linzmaier, Marion
Felten, Matthias
Zwarg, Jenny
Lennerz, Volker
Tüttenberg, Andrea
Stöcker, Walter
Title: How soluble GARP enhances TGFβ activation
Online publication date: 19-Aug-2022
Year of first publication: 2016
Language: english
Abstract: GARP (glycoprotein A repetitions predominant) is a cell surface receptor on regulatory T-lymphocytes, platelets, hepatic stellate cells and certain cancer cells. Its described function is the binding and accommodation of latent TGFβ (transforming growth factor), before the activation and release of the mature cytokine. For regulatory T cells it was shown that a knockdown of GARP or a treatment with blocking antibodies dramatically decreases their immune suppressive capacity. This confirms a fundamental role of GARP in the basic function of regulatory T cells. Prerequisites postulated for physiological GARP function include membrane anchorage of GARP, disulfide bridges between the propeptide of TGFβ and GARP and connection of this propeptide to αvβ6 or αvβ8 integrins of target cells during mechanical TGFβ release. Other studies indicate the existence of soluble GARP complexes and a functionality of soluble GARP alone. In order to clarify the underlying molecular mechanism, we expressed and purified recombinant TGFβ and a soluble variant of GARP. Surprisingly, soluble GARP and TGFβ formed stable non-covalent complexes in addition to disulfide-coupled complexes, depending on the redox conditions of the microenvironment. We also show that soluble GARP alone and the two variants of complexes mediate different levels of TGFβ activity. TGFβ activation is enhanced by the non-covalent GARP-TGFβ complex already at low (nanomolar) concentrations, at which GARP alone does not show any effect. This supports the idea of soluble GARP acting as immune modulator in vivo.
DDC: 570 Biowissenschaften
570 Life sciences
Institution: Johannes Gutenberg-Universität Mainz
Department: FB 04 Medizin
FB 10 Biologie
Place: Mainz
Version: Published version
Publication type: Zeitschriftenaufsatz
License: CC BY
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Journal: PLoS one
Pages or article number: e0153290
Publisher: PLoS
Publisher place: Lawrence, Kan.
Issue date: 2016
ISSN: 1932-6203
Publisher URL:
Publisher DOI: 10.1371/journal.pone.0153290
Appears in collections:DFG-OA-Publizieren (2012 - 2017)

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