Cyclosporin A impairs the secretion and activity of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeat)

Klilah Hershko, Vijaya L. Simhadri, Adam Blaisdell, Ryan C. Hunt, Jordan Newell, Sandra C. Tseng, Alon Y. Hershko, Jae Won Choi, Zuben E. Sauna, Andrew Wu, Richard J Bram, Anton A. Komar, Chava Kimchi-Sarfaty

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)44361-44371
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number53
DOIs
StatePublished - Dec 28 2012

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Thrombospondin 1
Disintegrins
Metalloproteases
Cyclosporine
Thrombotic Thrombocytopenic Purpura
Transplants
Peptidylprolyl Isomerase
Cyclophilins
Protein Folding
von Willebrand Factor
Isomerization
Platelets
Platelet Aggregation
Immunoprecipitation
Proline
Knockout Mice
Small Interfering RNA
Proteins
Peptide Hydrolases
Agglomeration

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Hershko, K., Simhadri, V. L., Blaisdell, A., Hunt, R. C., Newell, J., Tseng, S. C., ... Kimchi-Sarfaty, C. (2012). Cyclosporin A impairs the secretion and activity of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeat). Journal of Biological Chemistry, 287(53), 44361-44371. https://doi.org/10.1074/jbc.M112.383968

Cyclosporin A impairs the secretion and activity of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeat). / Hershko, Klilah; Simhadri, Vijaya L.; Blaisdell, Adam; Hunt, Ryan C.; Newell, Jordan; Tseng, Sandra C.; Hershko, Alon Y.; Choi, Jae Won; Sauna, Zuben E.; Wu, Andrew; Bram, Richard J; Komar, Anton A.; Kimchi-Sarfaty, Chava.

In: Journal of Biological Chemistry, Vol. 287, No. 53, 28.12.2012, p. 44361-44371.

Research output: Contribution to journalArticle

Hershko, K, Simhadri, VL, Blaisdell, A, Hunt, RC, Newell, J, Tseng, SC, Hershko, AY, Choi, JW, Sauna, ZE, Wu, A, Bram, RJ, Komar, AA & Kimchi-Sarfaty, C 2012, 'Cyclosporin A impairs the secretion and activity of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeat)', Journal of Biological Chemistry, vol. 287, no. 53, pp. 44361-44371. https://doi.org/10.1074/jbc.M112.383968
Hershko, Klilah ; Simhadri, Vijaya L. ; Blaisdell, Adam ; Hunt, Ryan C. ; Newell, Jordan ; Tseng, Sandra C. ; Hershko, Alon Y. ; Choi, Jae Won ; Sauna, Zuben E. ; Wu, Andrew ; Bram, Richard J ; Komar, Anton A. ; Kimchi-Sarfaty, Chava. / Cyclosporin A impairs the secretion and activity of ADAMTS13 (A disintegrin and metalloprotease with thrombospondin type 1 repeat). In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 53. pp. 44361-44371.
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abstract = "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.",
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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

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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.

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