USP4 Regulates Bone Function By SMURF1 And Mechanism Researching

Ubiquitination and deubiquitination systems play very important roles in the development,cell growth and differentiation,inflammation,tumor therapy and so on.We previous discovered that deubiquitination enzyme USP4 plays a role in the regulation of cell proliferation.We have therefore studied the regulation of USP4 in mouse organ development.We found that USP4 is highly expression in some organs,including the skeletal system.We constructed USP4 knockout mice and found that USP4 deletion causes increased mouse skeletal bone mass,in addition,we found that USP4 deletion cause osteoblast proliferation in vitro.We identified SMURF1 as a USP4 interacting protein by mass spectrometry.We then demonstrated that USP4 interacted directly with SMURF 1 by IP and pull down.We found that USP4 could stabilize SMURF 1 by promoting the deubiquitination of SMURF1 linked by K48 chain.In conclusion,we provide evidenve that USP4 binds directly to SMURF1 and catalyzes SMURF1 deubiquitination at the K48 chain,which inturn promotes SMURF1 stability and negatively regulates the skeletal system.Therefore,USP4 and its substrate proteins may serve as potential targets for the treatment of skeletal developmental defects.