Cyclosporin A impairs the secretion and activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat)
| Autor: | Adam Blaisdell, Richard J. Bram, Anton A. Komar, Alon Y. Hershko, Jae Won Choi, Zuben E. Sauna, Andrew Wu, Ryan C. Hunt, Sandra C. Tseng, Chava Kimchi-Sarfaty, Jordan Newell, Vijaya L. Simhadri, Klilah Hershko |
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| Rok vydání: | 2012 |
| Předmět: |
ADAMTS13 Protein
Down-Regulation Biochemistry Cyclophilins Mice Von Willebrand factor hemic and lymphatic diseases Cyclosporin a Prolyl isomerase Disintegrin polycyclic compounds Animals Humans Molecular Biology Mice Knockout Thrombospondin Metalloproteinase biology Metalloendopeptidases Molecular Bases of Disease Cell Biology Molecular biology ADAMTS13 Cell biology enzymes and coenzymes (carbohydrates) ADAM Proteins Protein Transport HEK293 Cells Chaperone (protein) biology.protein cardiovascular system Cyclosporine Protein Binding |
| Zdroj: | The Journal of biological chemistry. 287(53) |
| ISSN: | 1083-351X |
| Popis: | The protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat) cleaves multimers of von Willebrand factor, thus regulating platelet aggregation. ADAMTS13 deficiency leads to the fatal disorder thrombotic thrombocytopenic purpura (TTP). It has been observed that cyclosporin A (CsA) treatment, particularly in transplant patients, may sometimes be linked to the development of TTP. Until now, the reason for such a link was unclear. Here we provide evidence demonstrating that cyclophilin B (CypB) activity plays an important role in the secretion of active ADAMTS13. We found that CsA, an inhibitor of CypB, reduces the secretion of ADAMTS13 and leads to conformational changes in the protein resulting in diminished ADAMTS13 proteolytic activity. A direct, functional interaction between CypB (which possesses peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone functions) and ADAMTS13 is demonstrated using immunoprecipitation and siRNA knockdown of CypB. Finally, CypB knock-out mice were found to have reduced ADAMTS13 levels. Taken together, our findings indicate that cyclophilin-mediated activity is an important factor affecting secretion and activity of ADAMTS13. The large number of proline residues in ADAMTS13 is consistent with the important role of cis-trans isomerization in the proper folding of this protein. These results altogether provide a novel mechanistic explanation for CsA-induced TTP in transplant patients. |
| Databáze: | OpenAIRE |
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