Abstract：
: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.
journal_name
Mol Celljournal_title
Molecular cellauthors
Mandal P,Berger SB,Pillay S,Moriwaki K,Huang C,Guo H,Lich JD,Finger J,Kasparcova V,Votta B,Ouellette M,King BW,Wisnoski D,Lakdawala AS,DeMartino MP,Casillas LN,Haile PA,Sehon CA,Marquis RW,Upton J,Daley-Bauer LP,doi
10.1016/j.molcel.2014.10.021subject
Has Abstractpub_date
2014-11-20 00:00:00pages
481-95issue
4eissn
1097-2765issn
1097-4164pii
S1097-2765(14)00831-4journal_volume
56pub_type
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