Role Of E3 Ubiquitin Ligase Smurf1 In Regulating The Ubiquitination Of Receptor-interacting Protein RIP2

Protein ubiquitination is a dynamic post-translational modification that plays important roles in controlling cell-cycle progression,signal transduction,and transcriptional regulation.Ubiquitination has been shown associated with cancer,neurodegenerative diseases and high blood pressure,etc.The ubiquitination system has therefore become a hot target for developing anti-tumor drugs.Since being discovered,smurfl has been intensively studied and found that it is involved in regulating many important biological functions such as cell growth and morphogenesis,cell migration,cell polarity,and immune responses.Mechasrnim studies indicate that Smurfl regulates these biological functions through a diverse signaling pathways including BMP,TGF-?,Wnt,and MAPK pathway.Moreover,Smurfl can also target TRAF1-6 for degradation,hence affects NF-?B activation.Receptor-interacting protein 2(RIP2)belongs to the RIP kinase family.Early studies showed that overexpression of RIP2 could mediate TLR signal transduction by activating NF-?B.However,subsequent studies showed that upon activation by muramyl dipeptide(MDP),NODI and NOD2 interact with RIP2 to induce NF-?B activation in innate immune responses.Many molecules that interact with RIP2 are demonstrated to be involved in the regulation NOD signal transduction,including XIAP,which interacts with RIP2 to promote NOD signaling,suggesting a important role of RIP2 in innate immunity and inflammatory response.This study demonstrates that Smurfl interacts with RIP2 and mediates RIP2 ubiquitination both in vivo and vitro,therefore down-regulates the protein levels of RIP2,providing new clues for studying the regulation mechanism of RIP2 protein stability and the new insight for Smurfl in inflammatory signaling pathway.