cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

McComb, Scott; Cheung, Herman H.; Korneluk, Robert G.; Wang, Shaomeng; Krishnan, Lakshmi; Sad, Subash

doi:10.1038/cdd.2012.59

Cited by 127 publications

(98 citation statements)

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“…Treatment with a mimetic of the second mitochondrial activator of apoptosis (SMAC) induces regulated cell death of macrophages even in the absence of any PAMP stimulation, and this is induced by rapid degradation of cIAPs by SMAC. 29 Stimulation of macrophages with the SMAC mimetic, birinapant (BP) resulted in a significant loss of cell viability, which was further enhanced by co-treatment with zVAD, and was rescued by treatment with Nec-1 ( Figure 4a). Interestingly, RIPK1…”

Section: Resultsmentioning

confidence: 99%

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

et al. 2016

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Receptor interacting protein kinase 1 (RIPK1) participates in several cell signaling complexes that promote cell activation and cell death. Stimulation of RIPK1 in the absence of caspase signaling induces regulated necrosis (necroptosis), which promotes an inflammatory response. Understanding of the mechanisms through which RIPK1 promotes inflammation has been unclear. Herein we have evaluated the impact of a K45A mutation of RIPK1 on necroptosis of macrophages and the activation of inflammatory response. We show that K45A mutation of RIPK1 results in attenuated necroptosis of macrophages in response to stimulation with LPS, TNFα and IFNβ in the absence of caspase signaling. Impairment in necroptosis correlated with poor phosphorylation of RIPK1, RIPK3 and reduced trimerization of MLKL. Furthermore, K45A mutation of RIPK1 resulted in poor STAT1 phosphorylation (at S727) and expression of RANTES and MIP-1α following TNF-R engagement in the absence of caspase activation. Our results further indicate that in the absence of stimulation by pathogen-associated molecular patterns (PAMPs), cellular inhibitors of apoptotic proteins (cIAPs) prevent the K45-dependent auto-phosphorylation of RIPK1, leading to resistance against necroptosis. Finally, RIPK1K45A mice displayed attenuated inflammatory response in vivo as they were significantly resistant against endotoxin shock, but highly susceptible against a challenge with Salmonella typhimurium. This correlated with reduced expression of IL-1β and ROS, and poor processing of caspase 8 by RIPK1K45A macrophages. Overall, these results indicate that K45 mediated kinase activity of RIPK1 is not only important for necroptosis but it also has a key role in promoting cytokine signaling and host response to inflammatory stimuli. Apoptosis is considered as the predominant, programmed pathway of cell death; however, recently several pathways of regulated cell death have been shown to operate in cells that are considered highly inflammatory.1,2 Although apoptosis has a major role during fetal development, 3 regulated necrotic cell death does not appear to influence fetal development. 4 Interestingly, receptor interacting protein kinase 1 (RIPK1) deficiency cause embryonic lethality, suggesting a key role of RIPK1 in host survival. 5 Besides the kinase activity, RIPK1 appears to have a scaffolding function, which may influence immune homeostasis. 6,7 Depending on the interacting partners and posttranslational modifications, RIPK1 has a multifaceted role in cell signaling and cell survival.8 Following TNF-R1 signaling, RIPK1 transitions between pro-survival and pro-cell death signaling complexes. 9,10 Necroptosis is a form of regulated necrosis of cells that operates in the absence of caspase activity 9 and is initiated by the engagement of various TLRs or cytokine receptors.11 The first cardinal signaling step in necrosome signaling is the phosphorylation of RIPK1, which leads to RIPK1-RIPK3 interaction and phosphorylation of RIPK3.12 Although necroptotic signaling has been shown to be...

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Section: Resultsmentioning

confidence: 99%

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

et al. 2016

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“…CYLD is required for necroptosis induction by deubiquitinating RIP1, whereas the involvements of other deubiquitinating enzymes that trigger RIP1 deubiquitination such as A20, USP21 and cezanne in necroptosis induction are currently unknown (46)(47)(48)86). Inhibition of cIAP function, which is critical for RIP1 polyubiquitination, by genetic deletion or pharmacological methods, has been reported to sensitize cells to necroptotic cell death by preventing RIP1 K63-linked ubiquitination (49,78,(87)(88)(89)(90). RIP1 deubiquitination leads to the formation of complex II, which is composed of TRADD, FADD, RIP1 and caspase-8 (91).…”

Section: Mechanism Of Tnf-induced Necroptosismentioning

confidence: 99%

The roles of FADD in extrinsic apoptosis and necroptosis

et al. 2012

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Fas-associated protein with death domain (FADD), an adaptor that bridges death receptor signaling to the caspase cascade, is indispensible for the induction of extrinsic apoptotic cell death. Interest in the non-apoptotic function of FADD has greatly increased due to evidence that FADD-deficient mice or dominant-negative FADD transgenic mice result in embryonic lethality and an immune defect without showing apoptotic features. Numerous studies have suggested that FADD regulates cell cycle progression, proliferation, and autophagy, affecting these phenomena. Recently, programmed necrosis, also called necroptosis, was shown to be a key mechanism that induces embryonic lethality and an immune defect. Supporting these findings, FADD was shown to be involved in various necroptosis models. In this review, we summarize the mechanism of extrinsic apoptosis and necroptosis, and discuss the in vivo and in vitro roles of FADD in necroptosis induced by various stimuli.[BMB Reports 2012; 45(9): 496-508] INTRODUCTIONFas-associated protein with death domain (FADD) is a critical adaptor protein for death receptor (DR)-mediated apoptosis. FADD is composed of two domains called the death domain (DD) and death effector domain (DED). The DD of FADD binds to the DD of the death receptor and FADD recruits procaspase-8 through the DED-DED interaction, forming a death-inducing signaling complex (DISC), where procaspase-8 is activated by self-cleavage. Active caspase-8 cleaves downstream effector caspases such as caspase-3, -6, and -7, inducing apoptosis. Interestingly, FADD deficiency results in embryonic lethality, displaying a defect in immune homeostasis and immune cell proliferation despite the defect in inducing apoptosis. In addition, FADD is also implicated in non-apoptotic functions such as cell cycle progression, proliferation, autophagy, inflammation and innate immunity (1, 2). Particularly, FADD phosphorylation at Ser194 (pFADD) by several kinases is associated with its nuclear localization and cell cycle regulation (3-8). Although FADD and pFADD are often overexpressed in various tumors, their functions in cancer development or chemotherapy-sensitivity are still controversial (9-14). Recent strong evidence from in vivo mice studies suggested negative roles of FADD in RIP1-and RIP3-dependent necroptosis (15-18). DR-mediated caspase-8 activation requires FADD, and leads to the cleavage of RIP1, RIP3, and CYLD, preventing necroptosis (19)(20)(21)(22). Thus, FADD deficiency is thought to inhibit caspase-8 and subsequent apoptosis, but activate necroptosis. Since necroptosis can be initiated by various stimuli in a variety of cell types independently of DRs, the exact mechanisms and functions of FADD require further investigation. This review focuses on the recent discoveries about the roles of FADD in apoptosis and necroptosis in various models, and we refer the reader to two comprehensive reviews of the diverse functions of FADD (1, 2). EXTRINSIC APOPTOSIS Molecular mechanism of extrinsic apoptosisExtrinsic apoptosis, which is...

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“…On one hand, necroptotic cell death has been shown to aid in activating an immune response to some viruses (8,9). On the other hand, we have previously shown that increased necrotic cell death in cellular inhibitor of apoptosisdeficient macrophages results in impaired control of bacteria (10). In addition, necroptotic cell death has been shown to perpetuate various inflammatory pathologies (4,11).…”

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Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

McComb

Shutinoski

Thurston

et al. 2014

The Journal of Immunology

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It has recently been shown that programmed necrosis, necroptosis, may play a key role in the development of inflammation. Deciphering the regulation of this pathway within immune cells may therefore have implications in pathology associated with inflammatory diseases. We show that treatment of macrophages with the pan caspase inhibitor (zVAD-FMK) results in both increased phosphorylation and decreased cleavage of receptor interacting protein kinase-1 (Rip1), leading to necroptosis that is dependent on autocrine TNF signaling. Stimulation of cells with TLR agonists such as LPS in the presence of zVAD-FMK also induced Rip1-phosphorylation via a TNFR-independent mechanism. Further examination of Rip1 expression under these stimulatory conditions revealed a regulatory cleavage of Rip1 in macrophages that is not apparently attributable to caspase-8. Instead, we provide novel evidence that cysteine family cathepsins, which are highly abundant in myeloid cells, can also cleave Rip1 kinase. Using small interfering RNA knockdown, specific cathepsin inhibitors, and cell-free cleavage assays, we demonstrate that cysteine cathepsins B and S can directly cleave Rip1. Finally, we demonstrate that only through combined inhibition of cathepsins and caspase-8 could a potent induction of macrophage necroptosis be achieved. These data reveal a novel mechanism of regulation of necroptosis by cathepsins within macrophage cells.

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cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation

Cited by 127 publications

References 45 publications

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

K45A mutation of RIPK1 results in poor necroptosis and cytokine signaling in macrophages, which impacts inflammatory responses in vivo

The roles of FADD in extrinsic apoptosis and necroptosis

Cathepsins Limit Macrophage Necroptosis through Cleavage of Rip1 Kinase

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