IRAK2 Counterbalances Oncogenic Smurf1 In Colon Cancer By Dictating ER Stress

The endoplasmic reticulum is a cellular organelle with central roles in maintaining proteostasis.The accumulation of misfolded proteins in the ER lumen causes ER stress.Cells evoke an evolutionarily conserved adaptive signalling network’unfolded protein response’ to restore ER homeostasis,however,how the signaling network is delicately orchestrated remains largely veiled.Meanwhile,the HECT type E3 ligase Smad ubiquitylation regulatory factor 1(Smurfl)has been reported to play critical roles in several important biological pathways by targeting distinct substrates for ubiquitylation,including WFS1,a critical mediator of ER stress,whereas the regulation of Smurfl activity and abundance upon ER stress are poorly understood.Here,we identified Interleukin-1 Receptor Associated Kinase 2(IRAK2)as a novel modulator of Smurfl in response to ER stress-induced cell death.Mechanistically,IRAK2 phosphorylates Smurfl at threonine residues to promote its self-degradation by ubiquitylation,resulting in altered cascade of ER effectors to induce apoptosis.We further demonstrate that IRAK2 is inversely correlated with oncogenic smurfl in colorectal carcinomas.Taken together,these findings highlight a novel mechanism for the interplays of different branches of ER stress signaling network and rendering IRAK2 as a potential tumor suppressor to counterbalance oncogenic smurfl.