Fig. 4.

Proposed mechanism for the pH-responsive stabilization of PEPCK mRNA. Interactions between the cap binding proteins (4E and 4G) and the polyA binding protein (PABP) cause mRNA to form a circular structure that enhances translation. Both a stabilizing mRNA binding protein (HuR) and destabilizing mRNA binding protein (AUF1) bind to the adenylate-uridylate (AU)-rich sequences within the 3′-untranslated region (UTR) of the PEPCK mRNA during normal acid-base balance. This complex recruits a deadenylase (Deaden) that shortens the polyA tail and causes dissociation of the polyA binding proteins (PABPs). The deadenylated mRNA is degraded in processing bodies by decapping and degradation from the 5′-end. In response to metabolic acidosis, the extent of phosphorylation of HuR is decreased while AUF1 is phosphorylated at additional sites. These changes lead to increased binding of HuR and a remodeling of the HuR/AUF1 complex that is bound to the 3′-UTR of PEPCK mRNA. The new complex is less effective at recruiting deadenylase and thereby promotes stabilization of the PEPCK mRNA.