GARP Regulates the Bioavailability and Activation of TGFβ

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2012 Jan 27

PMID 22278742

Citations 104

Authors

Rui Wang

Jianghai Zhu

Xianchi Dong

Minlong Shi

Chafen Lu

Timothy A Springer

Affiliations

Soon will be listed here.

Abstract

Glycoprotein-A repetitions predominant protein (GARP) associates with latent transforming growth factor-β (proTGFβ) on the surface of T regulatory cells and platelets; however, whether GARP functions in latent TGFβ activation and the structural basis of coassociation remain unknown. We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFβ1 prodomain and that GARP with C192A and C331A mutations can also noncovalently associate with proTGFβ1. Noncovalent association is sufficiently strong for GARP to outcompete latent TGFβ-binding protein for binding to proTGFβ1. Association between GARP and proTGFβ1 prevents the secretion of TGFβ1. Integrin α(V)β(6) and to a lesser extent α(V)β(8) are able to activate TGFβ from the GARP-proTGFβ1 complex. Activation requires the RGD motif of latent TGFβ, disulfide linkage between GARP and latent TGFβ, and membrane association of GARP. Our results show that GARP is a latent TGFβ-binding protein that functions in regulating the bioavailability and activation of TGFβ.

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References

Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T . Latent TGF-β structure and activation. Nature. 2011; 474(7351):343-9. PMC: 4717672. DOI: 10.1038/nature10152. View

Khalil N . TGF-beta: from latent to active. Microbes Infect. 1999; 1(15):1255-63. DOI: 10.1016/s1286-4579(99)00259-2. View

Melton A, Bailey-Bucktrout S, Travis M, Fife B, Bluestone J, Sheppard D . Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. J Clin Invest. 2010; 120(12):4436-44. PMC: 2993595. DOI: 10.1172/JCI43786. View

Shull M, Ormsby I, Kier A, Pawlowski S, Diebold R, Yin M . Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature. 1992; 359(6397):693-9. PMC: 3889166. DOI: 10.1038/359693a0. View

Ollendorff V, Noguchi T, Delapeyriere O, Birnbaum D . The GARP gene encodes a new member of the family of leucine-rich repeat-containing proteins. Cell Growth Differ. 1994; 5(2):213-9. View

Yoshimura A, Wakabayashi Y, Mori T . Cellular and molecular basis for the regulation of inflammation by TGF-beta. J Biochem. 2010; 147(6):781-92. PMC: 2912031. DOI: 10.1093/jb/mvq043. View

Macaulay I, Tijssen M, Thijssen-Timmer D, Gusnanto A, Steward M, Burns P . Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Blood. 2006; 109(8):3260-9. PMC: 6485507. DOI: 10.1182/blood-2006-07-036269. View

Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D . Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2009; 106(32):13439-44. PMC: 2726405. DOI: 10.1073/pnas.0901965106. View

Brunner A, Marquardt H, Malacko A, Lioubin M, Purchio A . Site-directed mutagenesis of cysteine residues in the pro region of the transforming growth factor beta 1 precursor. Expression and characterization of mutant proteins. J Biol Chem. 1989; 264(23):13660-4. View

10.

Eswar N, John B, Mirkovic N, Fiser A, Ilyin V, Pieper U . Tools for comparative protein structure modeling and analysis. Nucleic Acids Res. 2003; 31(13):3375-80. PMC: 168950. DOI: 10.1093/nar/gkg543. View

11.

Wipff P, Rifkin D, Meister J, Hinz B . Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007; 179(6):1311-23. PMC: 2140013. DOI: 10.1083/jcb.200704042. View

12.

Abe M, Harpel J, Metz C, Nunes I, Loskutoff D, Rifkin D . An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal Biochem. 1994; 216(2):276-84. DOI: 10.1006/abio.1994.1042. View

13.

Xiao T, Takagi J, Coller B, Wang J, Springer T . Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics. Nature. 2004; 432(7013):59-67. PMC: 4372090. DOI: 10.1038/nature02976. View

14.

Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H . TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004; 172(2):834-42. DOI: 10.4049/jimmunol.172.2.834. View

15.

Ludbrook S, Barry S, Delves C, Horgan C . The integrin alphavbeta3 is a receptor for the latency-associated peptides of transforming growth factors beta1 and beta3. Biochem J. 2002; 369(Pt 2):311-8. PMC: 1223078. DOI: 10.1042/BJ20020809. View

16.

Annes J, Munger J, Rifkin D . Making sense of latent TGFbeta activation. J Cell Sci. 2002; 116(Pt 2):217-24. DOI: 10.1242/jcs.00229. View

17.

Rifkin D . Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem. 2004; 280(9):7409-12. DOI: 10.1074/jbc.R400029200. View

18.

Veldhoen M, Hocking R, Atkins C, Locksley R, Stockinger B . TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006; 24(2):179-89. DOI: 10.1016/j.immuni.2006.01.001. View

19.

Oida T, Weiner H . TGF-β induces surface LAP expression on murine CD4 T cells independent of Foxp3 induction. PLoS One. 2010; 5(11):e15523. PMC: 2991360. DOI: 10.1371/journal.pone.0015523. View

20.

Cepek K, Parker C, Madara J, Brenner M . Integrin alpha E beta 7 mediates adhesion of T lymphocytes to epithelial cells. J Immunol. 1993; 150(8 Pt 1):3459-70. View