How Soluble GARP Enhances TGFβ Activation

被引:17
作者
Fridrich, Sven [1 ]
Hahn, Susanne A. [2 ]
Linzmaier, Marion [1 ]
Felten, Matthias [1 ]
Zwarg, Jenny [3 ]
Lennerz, Volker [3 ]
Tuettenberg, Andrea [2 ]
Stoecker, Walter [1 ]
机构
[1] JGU Mainz, Inst Zool, Cell & Matrix Biol, Mainz, Germany
[2] Univ Hosp Mainz, Dermatol, Mainz, Germany
[3] Univ Hosp Mainz, Med Ctr 3, Mainz, Germany
关键词
REGULATORY T-CELLS; GROWTH-FACTOR-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; LATENT COMPLEX; EXPRESSION; PROTEINS; SURFACE; TGF-BETA-1; GENES; TREG;
D O I
10.1371/journal.pone.0153290
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
GARP (glycoprotein A repetitions predominant) is a cell surface receptor on regulatory Tlymphocytes, platelets, hepatic stellate cells and certain cancer cells. Its described function is the binding and accommodation of latent TGF beta (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 beta and GARP and connection of this propeptide to alpha(v)beta(6) or alpha(v)beta(8) integrins of target cells during mechanical TGF beta 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 beta and a soluble variant of GARP. Surprisingly, soluble GARP and TGF beta 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 beta activity. TGF beta activation is enhanced by the non-covalent GARP-TGF beta 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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页数:16
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