Polymorphism in the 3 '-untranslated region of TNF alpha mRNA impairs binding of the post-transcriptional regulatory protein HuR to TNF alpha mRNA

Tumor necrosis factor alpha (TNF alpha) acts as a beneficial mediator in th e process of host defence, In recent years major interest has focused on th e AU-rich elements (AREs) present in the 3'-untranslated region (3'-UTR) of TNF alpha mRNA as this region plays a pivotal role in post-transcriptional control of TNF alpha production, Certain stimuli, such as lipopolysacchari des, a component of the Gram-negative bacterial cell wall, have the ability to relinquish the translational suppression of TNF alpha mRNA imposed by t hese AREs in macrophages, thereby enabling the efficient production of the TNF alpha, In this study we show that the polymorphism (GAU trinucleotide i nsertional mutation) present in the regulatory 3'-UTR of TNF alpha mRNA of NZW mice results in the hindered binding of RNA-binding proteins, thereby l eading to a significantly reduced production of TNF alpha protein, We also show that the binding of macrophage proteins to the main ARE is also decrea sed by another trinucleotide (CAU) insertion in the TNF alpha 3'-UTR, One o f the proteins affected by the GAU trinucleotide insertional mutation was i dentified as HuR, a nucleo-cytoplasmic shuttling protein previously shown t o play a prominent role in the stability and translatability of mRNA contai ning AREs, Since binding of this protein most likely modulates the stabilit y, translational efficiency and transport of TNF alpha mRNA, these results suggest that mutations in the ARE of TNF alpha mRNA decrease the production of TNF alpha protein in macrophages by hindering the binding of HuR to the ARE.