Poly(ADP-ribosyl)ation (PARylation) is mainly catalysed by poly-ADP-ribose polymerase 1 (PARP1), whose role in gene transcription modulation has been well established. Here we show that, in response to LPS exposure, PARP1 interacts with the adenylateuridylate-rich element-binding protein embryonic lethal abnormal vision-like 1 (Elavl1)/human antigen R (HuR), resulting in its PARylation, primarily at site D226. PARP inhibition and the D226 mutation impair HuR's PARylation, nucleocytoplasmic shuttling and mRNA binding. Increases in mRNA level or stability of pro-inflammatory cytokines/chemokines are abolished by PARP1 ablation or inhibition, or blocked in D226A HuR-expressing cells. The present study demonstrates a mechanism to regulate gene expression at the post-transcriptional level, and suggests that blocking the interaction of PARP1 with HuR could be a strategy to treat inflammation-related diseases that involve increased mRNA stability.
Nature Communications 8 Article number:14632 (2017); Published: 8 March 2017; Updated: 31 March 2017 The original version of this Article contained an error in the spelling of post-transcriptional in the title of the paper. This has now been corrected in both the PDF and HTML versions of the Article.
The present study aimed to compare the molecular mechanisms of rheumatoid arthritis (RA) and osteoarthritis (OA). The microarray dataset no. GSE29746 was downloaded from Gene Expression Omnibus. After data pre-processing, differential expression analysis between the RA group and the control, as well as between the OA group and the control was performed using the LIMMA package in R and differentially expressed transcripts (DETs) with |log2fold change (FC)|>1 and P<0.01 were identified. DETs screened from each disease group were then subjected to functional annotation using DAVID. Next, DETs from each group were used to construct individual interaction networks using the BIND database, followed by sub-network mining using clusterONE. Significant functions of nodes in each sub-network were also investigated. In total, 19 and 281 DETs were screened from the RA and OA groups, respectively, with only six common DETs. DETs from the RA and OA groups were enriched in 8 and 130 gene ontology (GO) terms, respectively, with four common GO terms, of which to were associated with phospholipase C (PLC) activity. In addition, DETs screened from the OA group were enriched in immune response-associated GO terms, and those screened from the RA group were largely associated with biological processes linked with the cell cycle and chromosomes. Genes involved in PLC activity and its regulation were indicated to be altered in RA as well as in OA. Alterations in the expression of cell cycle-associated genes were indicated to be linked with the occurrence of OA, while genes participating in the immune response were involved in the occurrence of RA.
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