Roles Of REGγ In Signal Transduction And Its Pathophysiological Effects

REG γ, same as PSME3, PA28 γ, is one nuclear protein, first found in the patient serum of SLE patient. It can be recognized by immune system, so it’s also called Ki antigen. As a member of REG, REG γ can form the proteasome complex with 20S core protein, functioning as one kind of 11S regulator particle. REG γ can bind to several proteins and then mediate their degradation by the ubiquitin-ATP independent pathway. REG γ is linked to many diseases, such as cancer and early aging. It’s reported that REG γ can regulate cell cycle and apoptosis through the mediation of some key proteins. SRC-3 is an oncogene protein and associates with several cancers. REG y could inhibit the breast cancer by degrading SRC-3. This study is mainly about two different proteins:GSK3β and AMPK, which is related to mental disease and muscle endurance.As previous result in mice behavior research showed that REG γ KO mice has obvious schizophrenia like syndrome compared with REG γ WT mice. Previous study imply that schizophrenia patient often has higher GSK3β level and activity in hippocampus, consistent with the result in REG γ KO mice. The DNA chip research showed that GSK3β is the direct substrate of REG γ. We then found that GSK3P has higher expression in both mice brain tissue and several cell lines with REG γ knockdown, with β-catenin down regulated at the same time, but no obvious change in RNA level. β-catenin acts as an important factor in the normal neuron form. The Co-IP and immune fluorescence result imply that REG γ bind to GSK3β and affect its degradation and localization, then to activity. The study suggests a possible role of REG γ in mental disease and gives a reasonable possibility to the healing of SZ.As the center of whole body, brain can maintain the body balance by nervous-humoral regulation. We found that the activity of AMPK, the metabolic key protein, can be regulated by REG y directly in SH-SY5Y cell line.To detect whether this regulation exists broadly, we do another behavior test and several cell research. We found that REG y KO and WT mice are different in endurance ability. REG y KO mice are able to run a longer time and distance than WT mice in treadmill study. The SDH staining of exercised muscle showed that the activity of SDH in mitochondria is higher in REGγ KO mice, so that the mitochondria biological function is higher. We get the result that cell energy regulator AMPK has higher activity after fast condition and exercise in REG y KO mice. Some mitochondria related protein PGC1-α, MCD, CPT1-b, Nampt, MFN2 has higher RNA level. The results in different cell lines are consistent with it in mice. REG y KO cell line always have reaction to nutrient and chemical than normal cell line. These findings indicate a possible role of REGγ in energy regulation. Modulating the activity of REG y will do a different function to keep cell energy balance.