| First Author | Mandal P | Year | 2014 |
| Journal | Mol Cell | Volume | 56 |
| Issue | 4 | Pages | 481-95 |
| PubMed ID | 25459880 | Mgi Jnum | J:219498 |
| Mgi Id | MGI:5621078 | Doi | 10.1016/j.molcel.2014.10.021 |
| Citation | Mandal P, et al. (2014) RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell 56(4):481-95 |
| abstractText | Receptor-interacting protein kinase 3 (RIP3 or RIPK3) has emerged as a central player in necroptosis and a potential target to control inflammatory disease. Here, three selective small-molecule compounds are shown to inhibit RIP3 kinase-dependent necroptosis, although their therapeutic value is undermined by a surprising, concentration-dependent induction of apoptosis. These compounds interact with RIP3 to activate caspase 8 (Casp8) via RHIM-driven recruitment of RIP1 (RIPK1) to assemble a Casp8-FADD-cFLIP complex completely independent of pronecrotic kinase activities and MLKL. RIP3 kinase-dead D161N mutant induces spontaneous apoptosis independent of compound, whereas D161G, D143N, and K51A mutants, like wild-type, only trigger apoptosis when compound is present. Accordingly, RIP3-K51A mutant mice (Rip3(K51A/K51A)) are viable and fertile, in stark contrast to the perinatal lethality of Rip3(D161N/D161N) mice. RIP3 therefore holds both necroptosis and apoptosis in balance through a Ripoptosome-like platform. This work highlights a common mechanism unveiling RHIM-driven apoptosis by therapeutic or genetic perturbation of RIP3. |
