Steroid hormone rapid signaling: the pivotal role of S-palmitoylation

Nuclear receptors (NRs) comprise a large family of proteins essential to manipulate various aspects of human biology. The class III of the NR family includes steroid hormone receptors (SHRs) involved in embryonic development, maintenance of differentiated cellular phenotypes, metabolism, and cell death. Dysfunction of SHR signaling leads to proliferative, reproductive, and metabolic diseases. SHRs are ligand-activated transcription factors which regulate cellular processes by inducing genomic events. In addition, membrane-initiating non-genomic signals have been described for several SHRs. These non-genomic actions are independent of the SHR transcription activity and have been attributed to canonical SHRs and non-canonical hormone binding sites located at the plasma membrane. The molecular bases for SHR-plasma membrane association represent a debated issue. Here, we hypothesize that the SHR amino acid sequence homologous to that encompassing the S-palmitoylated Cys447 residue of human estrogen receptor alpha could represent a new consensus sequence for SHR S-palmitoylation. Reversible S-palmitoylation of SHRs could play a critical role in receptor localization at the plasma membrane and in rapid nongenomic signaling activation.