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2016 ; 11
(4
): e0153290
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How Soluble GARP Enhances TGF? Activation
#MMPMID27054568
Fridrich S
; Hahn SA
; Linzmaier M
; Felten M
; Zwarg J
; Lennerz V
; Tuettenberg A
; Stöcker W
PLoS One
2016[]; 11
(4
): e0153290
PMID27054568
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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 TGF?
(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 TGF? and GARP and connection of this propeptide to ?v?6 or ?v?8
integrins of target cells during mechanical TGF? 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 TGF? and a soluble variant of GARP. Surprisingly, soluble
GARP and TGF? 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 TGF? activity. TGF? activation is enhanced
by the non-covalent GARP-TGF? 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.
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