Post-transcriptional regulation of TNF-alpha production

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DESCRIPTION (provided by applicant): An adenine and uridine-rich element (ARE) located in the 3' untranslated region of TNF a transcripts regulates mRNA stability and translation in a way that prevents the overexpression of TNFa. ARE-dependent post-transcriptional control requires the activity of RNA-binding proteins that function as translational repressors (e.g. TIA-l and TIAR), rnRNA stabilizers (e.g. HuR) and mRNA destabilizers (e.g. AUF1 and TTP). Surprisingly little is known about how these ARE-binding proteins (ARE-BPs) interact to regulate the expression of TNFa. TIA-l (and/or TIAR) promote the general translational repression that accompanies environmental stress and the selective translational repression of TNFa that occurs in LPS-activated macrophages. Translationally repressed transcripts transiently accumulate at discrete cytoplasmic foci known as stress granules (SGs). We hypothesize that the SG functions as a translational checkpoint that determines whether TNFa transcripts are translated or degraded. We further propose that this decision is influenced by ARE-BPs that regulate transcript stability (e.g. HuR, AUF1 and TTP). We will test these hypotheses by determining: i) the effect of a TIA-l truncation mutant that inhibits the assembly of SGs on the production of TNFa, ii) the mRNA and protein composition of LPS-induced SGs in macrophages, iii) whether different functional classes of ARE-BPs bind to the TNFa ARE in a cooperative, non-cooperative or competitive manner, and iv) how different functional classes of ARE-Bps cooperate to regulate the production of TNFa. Completion of these aims will improve our understanding of how ARE-BPs interact to regulate the production of TNFa. These studies might also identify molecular targets for the development of orally available TNFa blockers that can be used to treat patients with rheumatoid arthritis.