Death-domain dimerization-mediated activation of RIPK1 controls necroptosis and RIPK1-dependent apoptosis

Significance While the critical role of RIPK1 kinase activity in mediating necroptosis and RIPK1-dependent apoptosis has been established, we still know little about how the nonkinase domains of RIPK1 regulate its kinase activity. Establishing the role of RIPK1-death domain (DD) in mediating RIPK1 activation and formation of complex II provides an important insight into the molecular mechanism by which RIPK1 is activated during the transition from complex I to complex II. These results suggest that RIPK1-DD self-association may provide an amplification mechanism to promote the activation of RIPK1 kinase activity for mediating signal transduction to lead to cell death. Our results also suggest that the activation of RIPK1 may be regulated by its concentration as increased expression of RIPK1 under pathological conditions may promote its dimerization and activation.