A1 Refereed original research article in a scientific journal

Extracellular citrullination inhibits the function of matrix associated TGF-beta




AuthorsSipila KH, Ranga V, Rappu P, Torittu A, Pirila L, Kapyla J, Johnson MS, Larjava H, Heino J

PublisherELSEVIER SCIENCE BV

Publication year2016

JournalMatrix Biology

Journal name in sourceMATRIX BIOLOGY

Journal acronymMATRIX BIOL

Volume55

First page 77

Last page89

Number of pages13

ISSN0945-053X

eISSN1569-1802

DOIhttps://doi.org/10.1016/j.matbio.2016.02.008


Abstract
In inflammatory arthritis peptidyl arginine deiminase (PAD) enzymes can citrullinate arginine residues in extracellular matrix (ECM) proteins, such as collagens and fibronectin. This may lead to the generation of anti-citrullinated protein antibodies, important diagnostic markers in rheumatoid arthritis. In addition, the citrullination may directly affect protein function. Based on structural analysis, we found that most ECM-associated growth factors (GFs) have arginine residues in their receptor recognition sites. Thus, they are potential functional targets of extracellular citrullination. To examine this further, we focused on the citrullination of transforming growth factor-beta s (TGF-beta), well-known ECM-associated GFs. PAD-treatment of CHO-LTBP1 cell derived matrix, rich with TGF-beta, decreased the level of TGF-beta activity as detected by HaCaT and MLEC-PAI-1/Lu reporter cells. Additional experiments indicated that PAD-treatment inhibits the integrin-mediated TGF-beta activation since PAD-treatment decreased the binding of integrin alpha V beta 6 ectodomain as well as integrin-mediated spreading of MG-63 and HaCaT cells to beta 1-latency associated peptide (TGF-beta 1 LAP). The citrullination of the RGD site, an important integrin recognition motif, was confirmed by mass spectrometry. Furthermore, the citrullination of active TGF-beta 1 inhibited its binding to recombinant TGF-beta receptor II, and prevented its ability to activate TGF-beta signaling. Thus, extracellular PAD activity can affect the function of ECM -associated growth factors by different mechanisms. Importantly, the citrullination of both latent and active TGF-beta has the potency to regulate the inflammatory process. (C) 2016 Elsevier B.V. All rights reserved.



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