TY - JOUR
T1 - Cyclosporin A impairs the secretion and activity of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeat)
AU - Hershko, Klilah
AU - Simhadri, Vijaya L.
AU - Blaisdell, Adam
AU - Hunt, Ryan C.
AU - Newell, Jordan
AU - Tseng, Sandra C.
AU - Hershko, Alon Y.
AU - Choi, Jae Won
AU - Sauna, Zuben E.
AU - Wu, Andrew
AU - Bram, Richard J.
AU - Komar, Anton A.
AU - Kimchi-Sarfaty, Chava
PY - 2012/12/28
Y1 - 2012/12/28
N2 - 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 knockout 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.
AB - 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 knockout 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.
UR - http://www.scopus.com/inward/record.url?scp=84871751028&partnerID=8YFLogxK
U2 - 10.1074/jbc.M112.383968
DO - 10.1074/jbc.M112.383968
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C2 - 23144461
AN - SCOPUS:84871751028
SN - 0021-9258
VL - 287
SP - 44361
EP - 44371
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 53
ER -