Post-translational modification of orphan nuclear receptors TR2 and TR4 - Ligand independent activities

Nuclear receptors (NRs) constitute one of the largest families of transcriptional regulators responding to certain physiological ligands, with 48 NRs identified in the human genome. Approximately one half of the members among this superfamily are orphan because they lack physiological ligands. Recent molecular and proteomic studies have uncovered extensive post-translational modifications (PTMs) on NRs, which can regulate the biological activities of many NRs. PTMs that exert functional consequences on NRs include phosphorylation, acetylation, ubquitination, SUMOylation and methylation. They affect receptor protein stability, ligand sensitivity, recruitment of co-regulators and sub-cellular distribution. Studies exploiting the biological effects induced by PTMs have begun to unravel novel functional roles for certain NRs. This is particularly significant for orphan NRs because their biological activities have been largely puzzling in the past. This review summarizes PTMs confirmed for two orphan NRs, Testis Receptor 2 (TR2) and 4 (TR4), and discusses the biological relevance of these PTMs.