The Regulation Of TNF-stimulated NF-?B Signaling Pathway By ITCH-mediated Ubiquitination Of TAB2 Protein

NF-?B signal transduction pathway is the main pathway by TNF activation.In general,Cells prefer to choose NF-?B pathway,as it was under TNF stimulation.For over the thirty years,the study of NF-?B pathway made great progress.It is obvious to all that NF-?B plays a vital role in immunity response,which regulated a various of level in immune system.Evolutionary conservation of NF-?B implied its function in cell,and so far,it remains to be resolved for the regulation of NF-?B pathway.In addition,it is known to us that ubiquitination is a significant important post-translation modification of protein.Many studies suggested that ubiquitination was a key mechanism,which was essential in signal transduction.At present,many scientific problems still exit,we could imagine without ubiquitination in vivo.In human,TAK1 is in control of cell survival and cell death.We encountered TAK1 binding protein 2(TAB2)via researching on TAK1 in our work.We observed that the interaction of both proteins will decrease TAB2 expression.Literatures have been reported that TAB2 combined with TAK1 through C-terminal domain,but no one can illustrate the function of TAK1-TAB 1/2/3 complex.This phenomenon occurs in this experiment to our eyes contact.We consumed that the reducing of TAB2 protein level was due to ubiquitin-proteasome pathway.And then,we proceeded to seek to the protein related to TAB2 protein degradation.Eventually,we found that E3 ubiquitin ligase ITCH regulated the degradation of TAB2,led to downregulation of NF-?B signal transduction pathway by TNF stimulation.And it made cell turn to death in the end.There is no doubt that TNF had meaningful function in immunity and inflammation,at the same time,inflammation was always involved in autoimmune disease,including in cancer,cardiovascular disease and rheumatoid arthritis and so on.Our research suggested that a novel mechanism in TNF-stimulated NF-?B signaling pathway is that regulated TAK1-TAB1/2/3 complex and speculated that ITCH-mediated ubiquitination of TAB2 protein resulted in downregulating in TNF-stimulated NF-?B signal transduction pathway.However,if the regulation of ITCH-mediated ubquitination of TAB2 was abnormal,NF-?B signal transduction pathway would be out of control.The excessive expression of NF-?B could cause disease and have an inestimable influence on human being.Perhaps we will benefit from this new mechanism in the future,which is in search of new drug target for diseases as well as provides a new destination.