The steroidal lactone withaferin A impedes T-cell motility by inhibiting the kinase ZAP70 and subsequent kinome signaling
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Title |
The steroidal lactone withaferin A impedes T-cell motility by inhibiting the kinase ZAP70 and subsequent kinome signaling
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Creator |
Mobashar Hussain Urf Turabe Fazil
Chandra Sekhar Chirumamilla Claudina Perez-Novo Brandon Han Siang Wong Sunil Kumar Siu Kwan Sze Wim Vanden Berghe Navin Kumar Verma |
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Subject |
T-cell Motility
Molecular Modelling Docking ZAP70 |
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Description |
Not Available
The steroidal lactone withaferin A (WFA) is a dietary phytochemical, derived from Withania somnifera. It exhibits a wide range of biological properties, including immunomodulatory, anti-inflammatory, antistress, and anticancer activities. Here we investigated the effect of WFA on T-cell motility, which is crucial for adaptive immune responses as well as autoimmune reactions. We found thatWFA dose-dependently (within the concentration range of 0.3–1.25 μM) inhibited the ability of human T-cells to migrate via cross-linking of the lymphocyte function-associated antigen-1 (LFA-1) integrin with its ligand, intercellular adhe sion molecule 1 (ICAM-1). Coimmunoprecipitation of WFA interacting proteins and subsequent tandem mass spectrometry identified a WFA-interactome consisting of 273 proteins in motile T-cells. In particular, our data revealed significant enrichment of the zeta-chain-associated protein kinase 70 (ZAP70) and cytoskeletal actin protein interaction networks upon stimulation. Phospho-peptide mapping and kinome anal ysis substantiated kinase signaling downstream of ZAP70 as a key WFA target, which was further confirmed by bait-pulldown and Western immunoblotting assays. The WFA-ZAP70 interaction was disrupted by a disulfide reducing agent dithiothreitol, sug gesting an involvement of cysteine covalent binding interface. In silico docking predicted WFA binding to ZAP70 at cystine 560 and 564 residues. These findings provide a mechanistic insight whereby WFA binds to and inhibits the ZAP70 kinase and im pedes T-cell motility. We therefore conclude that WFA may be exploited to pharmacologically control host immune responses and potentially prevent autoimmune-mediated pathologies Not Available |
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Date |
2022-05-21T05:12:48Z
2022-05-21T05:12:48Z 2021-11-03 |
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Type |
Research Paper
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Identifier |
Mobashar Hussain Urf Turabe Fazil, Chandra Sekhar Chirumamilla, Claudina Perez-Novo, Brandon Han Siang Wong, Sunil Kumar, Siu Kwan Sze, Wim Vanden Berghe, Navin Kumar Verma (2021). The steroidal lactone withaferin A impedes T-cell motility by inhibiting the kinase ZAP70 and subsequent kinome signaling, Journal of Biological Chemistry, 297(6), 101377.
0021-9258 http://krishi.icar.gov.in/jspui/handle/123456789/72347 |
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Language |
English
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Relation |
Not Available;
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Publisher |
Not Available
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