Please use this identifier to cite or link to this item:
https://hdl.handle.net/11000/30654
Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity
Title: Resveratrol targets PD-L1 glycosylation and dimerization to enhance antitumor T-cell immunity |
Authors: Verdura, Sara Cuyàs, Elisabet Cortada Almar, Eric Brunet, Joan López-Bonet, Eugeni Martín-Castillo, Begoña Bosch-Barrera, Joaquim Encinar, José Antonio MENÉNDEZ MENÉNDEZ, JAVIER ABEL |
Editor: Impact Journals |
Department: Departamentos de la UMH::Bioquímica y Biología Molecular |
Issue Date: 2019-12-23 |
URI: https://hdl.handle.net/11000/30654 |
Abstract:
New strategies to block the immune evasion activity of programmed death ligand-1 (PD-L1) are urgently needed. When exploring the PD-L1-targeted effects of mechanistically diverse metabolism-targeting drugs, exposure to the dietary polyphenol resveratrol (RSV) revealed its differential capacity to generate a distinct PD-L1 electrophoretic migration pattern. Using biochemical assays, computer-aided docking/molecular dynamics simulations, and fluorescence microscopy, we found that RSV can operate as a direct inhibitor of glyco-PD-L1-processing enzymes (α-glucosidase/α-mannosidase) that modulate N-linked glycan decoration of PD-L1, thereby promoting the endoplasmic reticulum retention of a mannose-rich, abnormally glycosylated form of PD-L1. RSV was also predicted to interact with the inner surface of PD-L1 involved in the interaction with PD-1, almost perfectly occupying the target space of the small compound BMS-202 that binds to and induces dimerization of PD-L1. The ability of RSV to directly target PD-L1 interferes with its stability and trafficking, ultimately impeding its targeting to the cancer cell plasma membrane. Impedance-based real-time cell analysis (xCELLigence) showed that cytotoxic T-lymphocyte activity was notably exacerbated when cancer cells were previously exposed to RSV. This unforeseen immunomodulating mechanism of RSV might illuminate new approaches to restore T-cell function by targeting the PD-1/PD-L1 immunologic checkpoint with natural polyphenols.
|
Keywords/Subjects: PD-L1 resveratrol immunotherapy T cells glycosylation |
Knowledge area: CDU: Ciencias puras y naturales: Biología: Bioquímica. Biología molecular. Biofísica |
Type of document: application/pdf |
Access rights: info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
DOI: https://doi.org/10.18632/aging.102646 |
Appears in Collections: Artículos Bioquímica y Biología Molecular
|
???jsp.display-item.text9???