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RIP3 induces apoptosis independent of pronecrotic kinase activity.

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.

SUBMITTER: Mandal P

PROVIDER: S-EPMC4512186 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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RIP3 induces apoptosis independent of pronecrotic kinase activity.

Mandal Pratyusha P Berger Scott B SB Pillay Sirika S Moriwaki Kenta K Huang Chunzi C Guo Hongyan H Lich John D JD Finger Joshua J Kasparcova Viera V Votta Bart B Ouellette Michael M King Bryan W BW Wisnoski David D Lakdawala Ami S AS DeMartino Michael P MP Casillas Linda N LN Haile Pamela A PA Sehon Clark A CA Marquis Robert W RW Upton Jason J Daley-Bauer Lisa P LP Roback Linda L Ramia Nancy N Dovey Cole M CM Carette Jan E JE Chan Francis Ka-Ming FK Bertin John J Gough Peter J PJ Mocarski Edward S ES Kaiser William J WJ

Molecular cell 20141120 4

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 ...[more]

PMID: 25459880

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RIP3 induces apoptosis independent of pronecrotic kinase activity.

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RIP3 induces apoptosis independent of pronecrotic kinase activity.

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