Proteomics

Dataset Information

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Withaferin A inhibits LFA-1-stimulated ZAP70 activity and T-cell motility


ABSTRACT: a steroidal lactone withaferin A (WFA) can inhibit T-cell motility, which is crucial for adaptive immune responses as well as autoimmune reactions. Tandem mass spectrometry identified WFA-interactome in human T-cells that were stimulated to migrate via cross-linking of the lymphocyte function-associated antigen-1 (LFA-1) integrin with the ligand intercellular adhesion receptor 1 (ICAM-1). Data revealed significant enrichment of the zeta-chain-associated protein kinase 70 (ZAP70) and cytoskeletal actin protein interaction networks. Phospho-peptide mapping and kinome analysis substantiated kinase signaling downstream of ZAP70 and cytoskeletal kinase pathways as key WFA targets, which was further confirmed by in silico analysis and molecular assays. The WFA-ZAP70 complex was disrupted by a redox agent dithiothreitol, suggesting a covalent binding interface. Moreover, WFA ablated the phosphorylation of the myosin light chain, further constraining T-cell motility. These studies identify a mechanism whereby WFA can impact T-cell motility. WFA can therefore be exploited to pharmacologically controlling host immune responses and preventing autoimmune-mediated pathologies.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Cell Culture

DISEASE(S): Disease Free

SUBMITTER: SoFong Cam Ngan  

LAB HEAD: Navin Kumar Verma

PROVIDER: PXD026508 | Pride | 2022-02-17

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
151105_Fazil_BTM-01.msf Msf
151105_Fazil_BTM-01_proteingroups_SwissprotHuman.txt Txt
151105_Fazil_BTM-01_psms_SwissprotHuman.txt Txt
151105_Fazil_BTM.raw Raw
151105_Fazil_BTR-01.msf Msf
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Publications

The steroidal lactone withaferin A impedes T-cell motility by inhibiting the kinase ZAP70 and subsequent kinome signaling.

Fazil Mobashar Hussain Urf Turabe MHUT   Chirumamilla Chandra Sekhar CS   Perez-Novo Claudina C   Wong Brandon Han Siang BHS   Kumar Sunil S   Sze Siu Kwan SK   Vanden Berghe Wim W   Verma Navin Kumar NK  

The Journal of biological chemistry 20211103 6


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 that WFA dose-dependently (within the concentration range of 0.3-1.25 μM) inhibited the ability of human T-cells  ...[more]

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