SUMO Modification Of IMPDH2 Regulates Its Enzyme Activity

Inosine monophosphate dehydrogenase(IMPDH)is an enzyme that catalyzes the conversion of inosine Monophosphate(IMP)to xanthine monophosphateformation(XMP)in an NAD-dependent manner.In the course of purine synthesis,IMPDH lies at the branch point of the synthesis of adenine and guanine nucleotides,and acts as a rate-limiting enzyme.Inhibition of the cellular activity of IMPDH is associated with the depletion of cell GTP levels,thereby leading to a remarkable cessation of DNA and RNA biosynthesis and the blockage of cell-cycle.It has been reported that IMPDH2 has higher activity and expression level in many fast dividing cells and cancer cells,its activity is very important not only for these cell's proliferation,but also for immune cells' survival.Therefore,IMPDH can be used as a drug target for effective antitumor and immune suppression.The inhibitor of IMPDH mycophenolic acid(MPA)has been widespread accepted in clinical.Sumoylation is a kind of post-translational modifications.The SUMO molecule can be covalently attached to its substrate proteins to regulate protein functions.Sumoylation modifies many proteins and participates in numerous cellular processes.In this study,we,for the first time,demonstrate that IMPDH2 can be sumoylated.It is further indicative that sumoylation of IMPDH2 is occurred at Lys62,and associated with IMPDH2 protein degradation,as well as its enzyme activity repression.Con-sistent with this function,the antitumor drug doxorubicin also shows to enhance the IMPDH2 sumoylation.Taken together,our study not only demonstrates IMPDH2 as a new substrate of sumoylation,but also verifies this process responsible for negative regulation of IMPDH2 activity.