Pick your poison: The Ripoptosome, a cell death platform regulating apoptosis and necroptosis

Feoktistova, Maria; Geserick, Peter; Panayotova-Dimitrova, Diana; Leverkus, Martin

doi:10.4161/cc.11.3.19060

Cited by 63 publications

(55 citation statements)

References 48 publications

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“…The precise cleavage and phosphorylation events that govern necrosome assembly and stability remain poorly understood, 34 but degradation of nascent RIPK3 complexes by the cIAPs has been shown to play a key role in the suppression of RIPK3 activation. 18,19,36 We were unable to recover stable RIPK1/RIPK3 complexes following RIPK3 dimerization in the presence of Nec1, consistent with degradation of these complexes. Notably, however, we found that chemically enforced oligomerization potentiated RIPK3 activation and eliminated the ability of caspase-8 and RIPK1 to control this process, despite their recruitment to RIPK3 oligomers.…”

Section: Discussionmentioning

confidence: 70%

RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis

et al. 2014

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Necroptosis is a form of programmed cell death that depends on the activation of receptor interacting protein kinase-1 (RIPK1) and RIPK3 by receptors such as tumor necrosis factor (TNF) receptor-1. Structural studies indicate that activation of RIPK3 by RIPK1 involves the formation of oligomers via interactions of the RIP homotypic interaction motif (RHIM) domains shared by both proteins; however, the molecular mechanisms by which this occurs are not fully understood. To gain insight into this process, we constructed versions of RIPK3 that could be induced to dimerize or oligomerize in response to a synthetic drug. Using this system, we find that although the formation of RIPK3 dimers is itself insufficient to trigger cell death, this dimerization seeds a RHIM-dependent complex, the propagation and stability of which is controlled by caspase-8 and RIPK1. Consistent with this idea, we find that chemically enforced oligomerization of RIPK3 is sufficient to induce necroptosis, independent of the presence of the RHIM domain, TNF stimulation or RIPK1 activity. Further, although RIPK1 contributes to TNF-mediated RIPK3 activation, we find that RIPK1 intrinsically suppresses spontaneous RIPK3 activation in the cytosol by controlling RIPK3 oligomerization. Cells lacking RIPK1 undergo increased spontaneous RIPK3-dependent death on accumulation of the RIPK3 protein, while cells containing a chemically inhibited or catalytically inactive form of RIPK1 are protected from this form of death. Together, these data indicate that RIPK1 can activate RIPK3 in response to receptor signaling, but also acts as a negative regulator of spontaneous RIPK3 activation in the cytosol.

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Section: Discussionmentioning

confidence: 70%

RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis

et al. 2014

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“…AIF-mediated glioma necrosis produced by UCD38B is independent of canonical apoptosis Pasupuleti et al, 2013) and appears to be distinct from ripoptosomemediated necroptosis (Feoktistova et al, 2012). RIP-1 inhibition by necrostatin does not alter the anticancer cytotoxicity of UCD38B .…”

Section: Ucd38b Alters Endosomal Trafficking In Gliomasmentioning

confidence: 92%

Mis-Trafficking of Endosomal Urokinase Proteins Triggers Drug-Induced Glioma Nonapoptotic Cell Death

2015

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5-Benzylglycinyl-amiloride (UCD38B) is the parent molecule of a class of anticancer small molecules that kill proliferative and nonproliferative high-grade glioma cells by programmed necrosis. UCD38B intracellularly triggers endocytosis, causing 40-50% of endosomes containing proteins of the urokinase plasminogen activator system (uPAS) to relocate to perinuclear mitochondrial regions. Endosomal "mis-trafficking" caused by UCD38B in human glioma cells corresponds to mitochondrial depolarization with the release and nuclear translocation of apoptotis-inducing factor (AIF) followed by irreversible caspaseindependent cell demise. High-content quantification of immunocytochemical colocalization studies identified that UCD38B treatment increased endocytosis of the urokinase plasminogen activator (uPA), its receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) into the early and late endosomes by 4-to 5-fold prior to AIF nuclear translocation and subsequent glioma demise. PAI-1 was found to comparably relocate with a subset of early and late endosomes in four different human glioma cell lines after UCD38B treatment, followed by caspase-independent, nonapoptotic cell death. Following UCD38B treatment, the receptor guidance protein LRP-1, which is required for endosomal recycling of the uPA receptor to the plasmalemma, remained abnormally associated with PAI-1 in early and late endosomes. The resultant aberrant endosomal recycling increased the total cellular content of the uPA-PAI-1 protein complex. Reversible inhibition of cellular endocytosis demonstrated that UCD38B bypasses the plasmalemmal uPAS complex and directly acts intracellularly to alter uPAS endocytotic trafficking. UCD38B represents a class of small molecules whose anticancer cytotoxicity is a consequence of causing the mis-trafficking of early and late endosomes containing uPAS cargo and leading to AIF-mediated necrotic cell death.

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“…interferon | MLKL | herpesvirus R eceptor interacting protein (RIP) kinase RIP1 (RIPK1) functions as an essential adapter in a number of innate immune signal transduction pathways, including those initiated by Toll-like receptor (TLR)3, TLR4, and retinoic acid-inducible gene 1 (RIG-I)-like receptors, in addition to death receptors (1)(2)(3)(4). Signaling via these pathways bifurcates at the level of RIP1 to produce opposing outcomes, a prosurvival inflammatory response counterbalanced by extrinsic cell death signaling that drives either apoptosis or necroptosis.…”

Section: Rip3mentioning

confidence: 99%

RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition

Kaiser

Daley‐Bauer

Thapa

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

263

287

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Significance The protein kinase receptor interacting protein 1 controls signaling via death receptors, Toll-like receptors, and retinoic acid-inducible gene 1-like receptors, dictating inflammatory outcomes as broad as cytokine activation and cell death. RIP1 makes a vital contribution during development, evident from the fact that RIP1-deficient mice die soon after birth. Here, we show that a kinase-independent function of RIP1 dampens the consequences of innate immune cell death. During parturition, RIP1 prevents the lethal consequences of RIP3-dependent necroptosis as well as caspase 8 (Casp8)-dependent apoptosis. In contrast to the RIP1-deficient phenotype, mice lacking a combination of RIP1, RIP3, and Casp8 are born and mature into viable, fertile, and immunocompetent adults. These results demonstrate the important protective role of RIP1 against physiologic and microbial death cues encountered at birth.

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Pick your poison: The Ripoptosome, a cell death platform regulating apoptosis and necroptosis

Cited by 63 publications

References 48 publications

RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis

RIPK1 both positively and negatively regulates RIPK3 oligomerization and necroptosis

Mis-Trafficking of Endosomal Urokinase Proteins Triggers Drug-Induced Glioma Nonapoptotic Cell Death

RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition

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