Deubiquitylase USP7 regulates human terminal erythroid differentiation by stabilizing GATA1

Ubiquitination is an enzymatic post-translational modification that affects protein fate. The ubiquitin-proteasome system was first discovered in reticulocytes where it plays important roles in reticulocyte maturation. Recent studies have revealed that ubiquitination is a dynamic and reversible process and that deubiquitylases are capable of removing ubiquitin from their protein substrates. Given the fact that the ubiquitin-proteasome system is highly active in reticulocytes, it is speculated that deubiquitylases may play important roles in erythropoiesis. Yet, the role of deubiquitylases in erythropoiesis remains largely unexplored. In the present study, we report that the expression of deubiquitylase USP7 is significantly increased during human terminal erythroid differentiation. We further show that interfering with USP7 function either by shRNA mediated knockdown or USP7 specific inhibitors impaired human terminal erythroid differentiation due to decreased GATA1 level and restoration of GATA levels rescues the differentiation defect. Mechanistically, USP7 deficiency led to decreased GATA1 protein level that can be reversed by proteasome inhibitors. Furthermore, USP7 interacts directly with GATA1 and catalyzes the removal of K48-linked polyubiquitylation chains conjugated onto GATA1, thereby stabilizing GATA1 protein. Collectively, our findings have identified an important role of a deubiquitylase in human terminal erythroid differentiation by stabilizing GATA1, the master regulator of erythropoiesis.