Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine that promotes eosinophil survival, maturation, and function. Factors, such as hyaluronic acid, that stimulate production of this cytokine are increased in asthmatic lung, as is the abundance of eosinophils. Eosinophils from asthmatic patients also exhibit elevated GM-CSF. Shen et al. show that Pin1, a peptidyl-prolyl isomerase specific for bonds between phosphorylated Ser-Pro or phosphorylated Thr-Pro, is part of a ribonucleoprotein complex that regulates the stability of GM-CSF mRNA. Pharmacological inhibition of Pin1 with juglone prevented increased mRNA abundance in and secretion of GM-CSF from isolated eosinophils in response to hyaluronic acid. The increase in GM-CSF mRNA was due to increased stability, not increased transcription. Pin1 coimmunoprecipitated with all four subunits of the AU-rich binding protein AUF1 (p45, p42, p40, and p37), of which p45 and p40 each have a potential Pin1 isomerization site. Hyaluronic acid triggered the dissociation of AUF1 from GM-CSF mRNA and the association of hnRNP C with GM-CSF mRNA, but only under conditions in which Pin1 was active. Hyaluronic acid stimulated the dephosphorylation of Pin1, which increased the activity of Pin1, and stimulated the phosphorylation of AUF1. In resting cells, the p37 subunit of AUF1 and Pin1 immunoprecipitated with the exosome-associated protein PM-Scl175, and hyaluronic acid decreased the association of p37 with the exosome. (The exosome is a complex associated with AU-rich mRNA decay.) Juglone blocked the prolonged survival observed for eosinophils isolated from allergen-challenged allergic donor patients, verifying the importance of Pin1 in vivo. The model for Pin1 in mRNA stability is as follows: In resting cells, Pin1 is inactive and the AUF1 complex recruits the exosome to decrease GM-CSF mRNA stability (see Anderson). Upon stimulation, Pin1 becomes dephosphorylated and AUF1 subunits are phosphorylated, leading to the release of the AUF1 complex from the mRNA and the binding of the hnRNP C, which promotes mRNA stability and allows increased production of the GM-CSF protein.
Z.-J. Shen, S. Esnault, J. S. Malter, The peptidyl-prolyl isomerase Pin1 regulates the stability of granulocyte-macrophage colony-stimulating factor mRNA in activated eosinophils. Nat. Immunol. 6, 1280-1287 (2005). [PubMed]
P. Anderson, Pin1: A proline isomerase that makes you wheeze? Nat. Immunol. 6, 1211-1212 (2005). [Online Journal]