Resveratrol post-transcriptionally regulates pro-inflammatory gene expression via regulation of KSRP RNA binding activity

6533b86cfe1ef96bd12c8368

RESEARCH PRODUCT

Resveratrol post-transcriptionally regulates pro-inflammatory gene expression via regulation of KSRP RNA binding activity

Julia Art Matthias Bros Katharina Schrick Felix Behnke Daniel Siuda Oliver Werz Huige Li Norbert Handler Franziska Bollmann Lorena Härdle Thomas Erker Hartmut Kleinert Bettina Mönch Andrea Pautz Florian Bauer Verena Besche Markus Hoffmann Ulrich Förstermann Verena M. Dirsch Jenny Henke Ching Yi Chen

subject

endocrine system diseases MRNA destabilization RNA Stability p38 mitogen-activated protein kinases Gene Expression RNA-binding protein Resveratrol Biology p38 Mitogen-Activated Protein Kinases Mice chemistry.chemical_compound Cell Line Tumor Stilbenes Gene expression Genetics Animals Humans ddc:610 RNA Messenger skin and connective tissue diseases Mice Knockout Messenger RNA Gene knockdown Exosome Multienzyme Ribonuclease Complex organic chemicals Anti-Inflammatory Agents Non-Steroidal Gene regulation Chromatin and Epigenetics RNA-Binding Proteins food and beverages Molecular biology 3. Good health Cell biology chemistry Resveratrol Mutation Trans-Activators Phosphorylation Inflammation Mediators hormones hormone substitutes and hormone antagonists

description

Resveratrol shows beneficial effects in inflammation-based diseases like cancer, cardiovascular and chronic inflammatory diseases. Therefore, the molecular mechanisms of the anti-inflammatory resveratrol effects deserve more attention. In human epithelial DLD-1 and monocytic Mono Mac 6 cells resveratrol decreased the expression of iNOS, IL-8 and TNF-α by reducing mRNA stability without inhibition of the promoter activity. Shown by pharmacological and siRNA-mediated inhibition, the observed effects are SIRT1-independent. Target-fishing and drug responsive target stability experiments showed selective binding of resveratrol to the RNA-binding protein KSRP, a central post-transcriptional regulator of pro-inflammatory gene expression. Knockdown of KSRP expression prevented resveratrol-induced mRNA destabilization in human and murine cells. Resveratrol did not change KSRP expression, but immunoprecipitation experiments indicated that resveratrol reduces the p38 MAPK-related inhibitory KSRP threonine phosphorylation, without blocking p38 MAPK activation or activity. Mutation of the p38 MAPK target site in KSRP blocked the resveratrol effect on pro-inflammatory gene expression. In addition, resveratrol incubation enhanced KSRP-exosome interaction, which is important for mRNA degradation. Finally, resveratrol incubation enhanced its intra-cellular binding to the IL-8, iNOS and TNF-α mRNA. Therefore, modulation of KSRP mRNA binding activity and, thereby, enhancement of mRNA degradation seems to be the common denominator of many anti-inflammatory effects of resveratrol.

year	journal	country	edition	language
2014-10-30	Nucleic Acids Research

https://doi.org/10.1093/nar/gku1033