Keratins regulate Hsp70-mediated nuclear localization of p38 Mitogen-activated protein kinase

Abstract

Intermediate filament protein keratin (K) 8 binds to Hsp70 and p38 MAPK, and is phosphorylated at Ser74 by p38. However, a p38 binding site on K8 and the molecular mechanism of K8-p38 interaction related to Hsp70 are unknown. Here, we identify a p38 docking site on K8 (Arg148/149 and Leu159/161) that is highly conserved in other intermediate filaments. The docking-deficient K8 mutation causes increased p38-Hsp70 interaction and enhanced p38 nuclear localization, indicating that the p38 dissociated from mutant K8 makes a complex with Hsp70, known as a potential chaperone for p38 nuclear translocation. Comparison of p38 MAPK binding with liver disease-associated keratin variants shows that K18-I150V variant dramatically reduces binding with p38, which is similar to the effect of the p38 docking-deficient mutation on K8. Since the p38 docking site on K8 (Arg148/149 and Leu159/161) and the K18-Ile150 residue are closely localized in parallel K8/K18 heterodimer, the K18-I150V mutation may interfere K8-p38 interaction. These findings show that keratins modulate the p38 nuclear localization, functioning as a cytoplasmic anchor for p38, which might affect a number of p38-mediated signal transduction pathways.