Crucial Roles of the RIP Homotypic Interaction Motifs of RIPK3 in RIPK1-Dependent Cell Death and Lymphoproliferative Disease

Receptor-interacting protein kinase 3 (RIPK3) has been identified as an essential regulator of necroptosis, apoptosis, and inflammatory signaling. RIPK3 contains an N-terminal kinase domain and a C-terminal RIP homotypic interaction motif (RHIM). However, the physiological roles of RIPK3 RHIM remain unclear. Here we generate knockin mice endogenously expressing the RIPK3 RHIM mutant, RIPK3 V448P . Cells expressing RIPK3 V448P are resistant to RIPK1 kinase-dependent apoptosis and necroptosis, and Ripk3 V448P/V448P mice rescue embryonic lethality of Fadd -deficient mice by intercrossing. Strikingly, Ripk3 V448P/V448P Fadd −/− mice display more severe lymphoproliferative disease with a marked increase in abnormal CD3 + B220 + lymphocytes compared with Ripk3 −/− Fadd −/− mice. More importantly, these inflammatory morbidities in Ripk3 V448P/V448P Fadd −/− mice are profoundly inhibited by additional deletion of Ripk1 . Taken together, these results reveal a previously unidentified physiological function of RHIM of RIPK3 in regulating RIPK1-dependent cell death and lymphoproliferative disease.