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

Abstract

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.

Transcriptomic analysis identifies a role of PI3K–Akt signalling in the responses of skeletal muscle to acute hypoxia in vivo

“…A significant decrease in Akt phosphorylation was observed by 2 h of hypoxia. So we considered interactions between RNA-binding proteins (BP) and genes with AU-rich elements (ARE) in their 3ʹUTRs, where ARE-binding proteins such as BRF1 have been identified as targets of Akt (Day & Tuite, 1998;Graham et al 2010;Bollmann et al 2014;Hausburg et al 2015). We confirmed that BRF1 phosphorylation was significantly decreased after 2 h of hypoxia in mouse skeletal muscle following a time course similar to that of Akt phosphorylation.…”

Antioxidant effects of resveratrol in the cardiovascular system

“…Resveratrol has been shown to induce various biological effects in preclinical studies. This is probably because resveratrol is a molecule with many targets (Bollmann et al , ). Resveratrol is relatively hydrophobic because of its planar stilbene motif.…”

Diverse roles of the nucleic acid‐binding protein KHSRP in cell differentiation and disease

“…Linker et al reported that ZFP36 [also known as TTP, an RNA‐binding protein (RBP) that usually promotes decay of ARE‐containing labile mRNAs] enhances NOS2A mRNA stability by interacting with KHSRP and hijacking the KHSRP–exosome complex away from NOS2A mRNA in colorectal adenocarcinoma cells. More recently, the same group has reported that KHSRP represents a pivotal element for the anti‐inflammatory function of resveratrol, a natural phenol produced by plants in response to injury or upon invasion by bacteria or fungi. Resveratrol has been proved to have beneficial effects on cancer or cardiovascular diseases.…”