Pin1 regulates parathyroid hormone mRNA stability

Abstract

Secondary hyperparathyroidism often occurs in chronic kidney disease (CKD) and vitamin D deficiency, resulting in increased fractures and mortality. Understanding factors that stimulate parathyroid hormone (PTH) synthesis is important for devising methods to treat this condition. Previous work has demonstrated that murine Pth mRNA levels are regulated by proteins that bind AU-rich elements (AREs) within the 3' UTR region of Pth mRNA and influence Pth mRNA stability. In this issue of the JCI, Nechama et al. demonstrate that in murine secondary hyperparathyroidism associated with CKD or Ca deficiency, the activity of Pin1, a peptidyl-prolyl isomerase, is reduced (see the related article beginning on page 3102). Reduced Pin1 activity resulted in the phosphorylation and degradation of an ARE-binding protein, K-homology splicing regulator protein (KSRP), which normally enhances the degradation of Pth mRNA. The activity of other ARE-binding proteins, such as AU-rich binding factor 1 (AUF1), that increase Pth mRNA stability, was increased, thereby increasing PTH synthesis. This work suggests new ways by which to regulate PTH synthesis in secondary hyperparathyroidism.

Figure 1. Cellular processing of RNA.

Following transcription, nascent RNA comprised of exons (E1–E4) and intervening sequences (IVS) is processed in the nucleus by 5′ methyl capping, splicing, cleavage, and polyadenylation. Processed RNA is exported from the nucleus and binds various structural elements and binding proteins. ARE-BPs (purple box and red oval) bind to AREs within the 3′ region of RNA and stabilize or destabilize mRNA. Stabilized RNA undergoes translation in ribosomes, whereas destabilized RNA undergoes deadenylation, decapping, and degradation in exosomes or P-bodies.

Figure 2. Processing of Pth mRNA.

Murine Pth mRNA is bound by ARE-BPs, which either stabilize or destabilize Pth mRNA, thereby altering Pth mRNA half-life. The ratio of activities of stabilizing/destabilizing ARE-BPs bound to Pth mRNA determines the half-life of a given Pth mRNA molecule. KSRP is a Pth mRNA–destabilizing ARE-BP that is active in its dephosphorylated state. In their new study in this issue of the JCI, Nechama et al. (46) report that the peptidyl-prolyl isomerase Pin1 is responsible for the dephosphorylation of KSRP. In CKD, Pin1 activity is reduced, and as a result, less dephosphorylated (active) KSRP is available. As a consequence, a stabilizing ARE-BP, AUF1, is active and Pth mRNA is degraded to a lesser extent, resulting in higher intracellular Pth mRNA levels, more PTH synthesis, and secondary hyperparathyroidism. P, phosphate.