Distinct functions of RIP1 in immune homeostasis revealed using novel animal models

Abstract

Abstract RIP1 was originally identified as a protein associated with Fas and TNFR1, which can trigger apoptosis. However, initial studies indicated that RIP1 is dispensable for apoptotic signaling. Instead, cells lacking RIP1 are defective in TNFR1-induced activation of NF-kB, a critical player involved in pro-survival signaling. Recent studies indicate that a certain form of necrosis-like death, necroptosis, requires RIP1. In contrast, the Fas-associated death domain (FADD) protein appears to play an obligatory role in apoptosis induced by Fas and TNFR1. However, the embryonic lethality phenotype of fadd−/− mice had remained a long-standing enigma, until analysis was performed to induce simultaneous deletion of both FADD and RIP1. The resulting fadd−/−rip1−/− double mutant mice displayed normal embryogenesis, indicating that fadd−/− embryos die of RIP1-dependent necroptosis. On the other hand, absence of RIP1 blocks postnatal development. Most recently, studies including ours demonstrated that only when both FADD and RIP3 were deleted will rip1−/− mice survive to adulthood. This result indicates perinatal lethality in RIP1-deficient mice is due to not only FADD-mediated apoptosis but also RIP3-dependent necrosis. Interestingly, we found that lack of RIP1 greatly diminished lymphoaccumulation disease in fadd−/−rip3−/− mice. To investigate RIP1 functions in adult immune cells, we performed conditional deletion of RIP1 in lineage committed lymphoid cells. Viable hypomorphic mutant mice with selective loss of function were employed to delineate the complex signaling pathways mediated by RIP1 in vivo. The results revealed a novel mechanism in the adult lymphoid system, which is distinct from the role of RIP1 in neonatal cells.