SDF‐1α induces differential trafficking of CXCR4‐CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival. Issue 7 (25th March 2014)

• Record Type: Journal Article
• Authors: Chatterjee, Madhumita; Seizer, Peter; Borst, Oliver; Schönberger, Tanja; Mack, Andreas; Geisler, Tobias; Langer, Harald F.; May, Andreas E.; Vogel, Sebastian; Lang, Florian; Gawaz, Meinrad
• Is Part Of: FASEB journal. Volume 28:Issue 7(2014)
• Page Start: 2864
• Page End: 2878
• Publication Date: 2014-03-25
• Subjects: platelets -- chemokine -- receptor -- apoptosis; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.14-249730
• Languages: English
• ISSNs: 0892-6638

Abstract

ABSTRACT: Platelet‐derived SDF‐1α (CXCL12) mediates inflammatory and regenerative mechanisms. The present study characterizes the effect of SDF‐1α ligation in platelets. SDF‐1α (0–100 μM) dose and time dependently caused internalization of its receptor CXCR4 (28.9±1.6 vs . 16.1±1.9 in SDF‐1α‐treated platelets), coupled to the surface externalization of CXCR7 (65.5±8 vs . 162.8±27.6 following SDF‐1α treatment), both in vitro and in vivo . This was inhibited in the presence of AMD3100 (100 μM), CXCR4 blocking and vesicular transport inhibitors (brefeldin A, 10 μM; rapamycin, 100 nM). SDF‐1α/CXCR‐4‐mediated CXCR7 translocation was significantly reduced by inhibitors of ERK1/2‐(U0126‐10 μM) and cyclophilinA (CyPA)‐(NIM811‐10 μM) by 28 and 46%, respectively. Further, SDF‐1α‐induced downstream phosphorylation of Erk1/2 led to CyPA‐dependent ubiquitination of CXCR7, which is essential for its surface translocation. CyPA‐PPIase‐activity inhibitor NIM‐811, Erk1/2, and E1‐ligase inhibitor‐(PYR‐41‐25 μM) significantly abolished SDF‐1α‐driven CXCR7 ubiquitination and subsequent surface translocation. SDF‐1α induced CXCR7 ubiquitination, and its surface exposure was observed in wild‐type murine platelets, but not in CyPA‐deficient platelets. SDF‐1α/CXCR4‐CyPA‐dependent CXCR7 translocation and its subsequent ligation attenuated activation‐induced apoptosis both in vitro and when administered in vivo . This antiapoptotic effect of SDF‐1α was abrogated by blocking CXCR7, also significantly affected in Cypa –/– platelets. Thus, we decipher a novel mechanism, whereby SDF‐1α regulates relative receptor availability in circulating platelets and exerts its prosurvival benefits.—Chatterjee, M., Seizer, P., Borst, O., Schönberger, T., Mack, A., Geisler, T., Langer, H. F., May, A. E., Vogel, S., Lang, F., Gawaz, M. SDF‐1α induces differential trafficking of CXCR4‐CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival. FASEB J . 28, 2864–2878 (2014). www.fasebj.org