SUMOylation In REGγ Modulates Its Biological Functions

REGγ, as a proteasome activator, can bind with20S proteasome core to degrade intact target proteins in an ATP-/ubiquitin-independent pathway. The target proteins of REGγ contain SRC-3, p21, HCV etc. Through degrading and regulating these proteins, REGγ is involved in cell cycle, cell apoptosis, tumorigenesis and other pathological and physiological processes to develop its biological functions. However, there are few reports about the modification and regulation of REGγ. In this study, we first explore the SUMOylation of REGγ and its functions. Then we studied the functions of REGγ in pathological and physiological processes in three directions.REGγ is found having interaction with PIAS1, a SUMO ligase E3, in yeast two hybrid system. Also, in vitro and in vivo tests show that REGy and PIAS1can bind with each other. REGγ is modified by SUMO1, SUM02, and SUM03in cells and in vitro, and PIAS1is its specific SUMO ligase E3, which can promote REGγ’s SUMOylation. SUMO modification occurs at multiple lysine sites of REGγ and the K6and K14are the essential sites for SUMOylation. SUMOylation influences REGγ’s intracellular localization and makes REGγ export from nucleus to cytoplasm. REGγ becomes more stable and has a longer half-life in SUMOylation status than in normal status. The SUMO modification sites are crucial for the targets binding and degradation activity of REGγ.REGγ regulates other proteins to play an important role in biological process. First, blocking the expression of REGγ causes the high level of p53and restrains tumor cells’ growth. This also makes cells tend to apoptosis under induction. Second, REGγ indirectly regulates PLZF, the spermatogonia stem cell marker, through p53to influence male mouse reproduction. Last, in autoimmune disease EAE mouse model, knocking down REGγ relieves the clinical symptoms of EAE, but the mechanism is still unclear.In summary, this study explores the mechanism of REGγ SUMOylation and regulation and the functions of REGγ in pathological and physiological processes.