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Translation control of gene expression is mediated by the signal-dependent binding of microRNAs and regulatory proteins to mRNAs. We have tried to systematically understand the integration of these two modes of control in the regulation of inflammatory gene expression. Translation regulation of pro-inflammatory genes plays an important role in the inflammatory response and disruption of such regulatory mechanisms leads to chronic inflammatory conditions, including cancer. The pro-inflammatory tumor suppressor protein PDCD4 plays an important role in maintaining the balance between inflammation and tumorigenesis. miR-21, an oncogenic miRNA upregulated in many cancers, inhibits the translation of PDCD4 mRNA. We found AU-rich element-binding protein HuR to interact with the PDCD4 3'UTR and prevent miR-21-mediated repression of PDCD4 translation. A cell line stably expressing miR-21 showed higher rate of proliferation and reduced apoptosis, which was reversed by HuR expression. Treatment with an inflammatory agonist, LPS, caused nuclear-cytoplasmic relocalization of HuR, and rescued the translation repression of PDCD4. Unprecedentedly, HuR was found to bind to miR-21 directly, and independently of PDCD4 mRNA, thereby sequestering it and preventing its interaction with the PDCD4 mRNA 3'UTR, leading to the rescue of translation. A qPCR array-based analysis showed significant association with HuR of around 30 miRNAs upregulated under inflammatory condition, indicating an “inflammatory miRNA interactome” of HuR. This suggests that HuR might act as a "miRNA sponge" to sequester multiple miRNAs and modulate miRNA-mediated translation regulation, resulting in fine-tuned gene expression in complex regulatory environments. |