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Identification of RIP3, a RIP-like kinase that activates apoptosis and NFκB

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Current Biology (Impact Factor: 9.92). 06/1999; 9(10):539-42. DOI: 10.1016/S0960-9822(99)80239-5
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ABSTRACT The tumor necrosis factor receptor 1 (TNFR1) and the Fas receptor recruit complexes formed by the interactions between RIP kinase, TRADD, FADD and RAIDD - adaptor proteins that contain death domains - which in turn recruit other proteins to initiate signaling [1][2][3][4][5]. To identify proteins associated with the TNF signaling pathway, we performed a yeast two-hybrid interaction screen using RIP as bait. We isolated a kinase, RIP3, which shares homology with the kinase domain of RIP and RIP2 (also known as Rick or CARDIAK). RIP3 could be co-immunoprecipitated with RIP, TRAF2 and TNFR1 in mammalian cells. The carboxy-terminal domain of RIP3, like that of RIP, could activate the transcription factor NFkappaB and induce apoptosis when expressed in mammalian cells. Interestingly, this region shares no significant sequence homology to the death domain of RIP, the caspase-recruiting domain (CARD) of RIP2 [6][7][8] or any other apoptosis-inducing domain. As with RIP and RIP2, the kinase domain of RIP3 was not required for either NFkappaB activation or apoptosis induction. Overexpression of a dominant-negative mutant of RIP3 strongly inhibited the caspase activation but not the NFkappaB activation induced by TNFalpha. Therefore, RIP3 appears to function as an intermediary in TNFalpha-induced apoptosis.

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Available from: Donald G Payan, Mar 14, 2014
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    • "Other kinase-dead mutants K51A, D161G, and D143N only drive this oligomerization when high concentrations of RIP3i compound are present. WT RIP3 has a propensity to drive this same process when overexpressed (Kasof et al., 2000; Pazdernik et al., 1999; Sun et al., 1999; Yu et al., 1999). "
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    • "Early experiments using overexpression systems implicate RIP3 in apoptosis and NF-kB signaling (Sun et al. 1999; Yu et al. 1999; Meylan et al. 2004). However, RIP3 À/À thymocytes responded normally to different apoptosis stimuli, and RIP3 À/À fibroblasts or macrophages were normal for TNF-and toll-like receptor (TLR) ligand-induced NF-kB activation (Newton et al. 2004). "
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    ABSTRACT: The receptor-interacting protein kinase 3 (RIP3/RIPK3) has emerged as a critical regulator of programmed necrosis/necroptosis, an inflammatory form of cell death with important functions in pathogen-induced and sterile inflammation. RIP3 activation is tightly regulated by phosphorylation, ubiquitination, and caspase-mediated cleavage. These post-translational modifications coordinately regulate the assembly of a macromolecular signaling complex termed the necrosome. Recently, several reports indicate that RIP3 can promote inflammation independent of its pronecrotic activity. Here, we review our current understanding of the mechanisms that drive RIP3-dependent necrosis and its role in different inflammatory diseases.
    Genes & development 08/2013; 27(15):1640-9. DOI:10.1101/gad.223321.113 · 12.64 Impact Factor
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    • "The structural basis for the association between RIP1 and RIP3 within the necrosome is poorly understood. Both RIP1 and RIP3 contain Ser/Thr kinase domains (KDs) at their N-termini, and RIP1 also has a death domain (DD) at its C terminus for recruitment to the TNF receptor signaling complex (Stanger et al., 1995; Sun et al., 1999; Yu et al., 1999) and for formation of the Ripoptosome (Feoktistova et al., 2011; Tenev et al., 2011; Wang et al., 2008) (Figure 1A). Unique segments of homologous sequences in RIP1 and RIP3 (RIP homotypic interaction motifs, RHIMs) (Figures 1A and 1B) were shown to mediate their interaction (Sun et al., 2002), which is crucial for the induction of programmed necrosis (Cho et al., 2009). "
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    ABSTRACT: RIP1 and RIP3 kinases are central players in TNF-induced programmed necrosis. Here, we report that the RIP homotypic interaction motifs (RHIMs) of RIP1 and RIP3 mediate the assembly of heterodimeric filamentous structures. The fibrils exhibit classical characteristics of β-amyloids, as shown by Thioflavin T (ThT) and Congo red (CR) binding, circular dichroism, infrared spectroscopy, X-ray diffraction, and solid-state NMR. Structured amyloid cores are mapped in RIP1 and RIP3 that are flanked by regions of mobility. The endogenous RIP1/RIP3 complex isolated from necrotic cells binds ThT, is ultrastable, and has a fibrillar core structure, whereas necrosis is partially inhibited by ThT, CR, and another amyloid dye, HBX. Mutations in the RHIMs of RIP1 and RIP3 that are defective in the interaction compromise cluster formation, kinase activation, and programmed necrosis in vivo. The current study provides insight into the structural changes that occur when RIP kinases are triggered to execute different signaling outcomes and expands the realm of amyloids to complex formation and signaling.
    Cell 07/2012; 150(2):339-50. DOI:10.1016/j.cell.2012.06.019 · 33.12 Impact Factor
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