Heat shock affects trafficking of DAX-1 by inducing its rapid and reversible cytoplasmic localization

Abstract

DAX-1 is an unusual orphan nuclear receptor whose mutations cause adrenal hypoplasia congenita (AHC) associated with hypogonadotropic hypogonadism (HHG). Subcellular localization of DAX-1 is a critical determinant of its biological activity. Indeed, the missense mutants found in AHC patients have an impaired transcriptional repressor activity due to protein misfolding and shift of their localization to the cytoplasm. For this reason, we sought to identify factors that regulate DAX-1 subcellular localization. Of several stimuli and chemical compounds tested, heat shock was the only stimulus able to induce rapid and massive relocalization of DAX-1 in the cytoplasm. The heat shock effect is reversible and does not involve stimulation of the p38 and ERK pathways. Heat shock probably acts by inducing modifications of DAX-1 and increasing its partitioning in the insoluble cellular fraction.