Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

Philip, Naomi H.; Dillon, Christopher P.; Snyder, Annelise G.; Fitzgerald, Patrick; Wynosky-Dolfi, Meghan A.; Zwack, Erin E.; Hu, Baofeng; Fitzgerald, Louise; Mauldin, Elizabeth A.; Copenhaver, Alan M.; Shin, Sunny; Wei, Lei; Parker, Matthew; Zhang, Jinghui; Oberst, Andrew; Green, Douglas R.; Brodsky, Igor E.

doi:10.1073/pnas.1403252111

Cited by 222 publications

(285 citation statements)

References 43 publications

(62 reference statements)

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“…49 Although caspase 1/11 signaling promotes canonical inflammasome signaling, caspase 8 and other members of the ripoptosome complex have also been shown to promote inflammasome activation. [50][51][52][53][54] Our results show that caspase 8 activity was reduced in RIPK1 K45A macrophages, which may limit IL-1β processing in RIPK1 K45A macrophages. We observed that the activity of caspase 8 was reduced in macrophages following infection with ST. Interestingly, caspase 1, which is activated during infection with ST, has been previously shown to limit the processing of various caspases.…”

Section: Ripk1 Interacts With Various Proteins Such As Ciaps Andmentioning

confidence: 66%

“…9,56 Although RIPK3 is a key component of the necrosome complex, and we have previously shown that RIPK3 is activated following ST infection, 57 RIPK3 has also been shown to promote inflammasome signaling. 11,50,51,53 More recently, MLKL, another member of the necrosome, has also been shown to promote inflammasome signaling, 58 indicating that there is significant overlap in inflammasome and necrosome signaling. We have previously shown that WT and RipK3 − / − mice harbor similar bacterial burden at day 5 postinfection with ST, 57 whereas, in our current study, the bacterial burden in RIPK1…”

Section: Ripk1 Interacts With Various Proteins Such As Ciaps Andmentioning

confidence: 99%

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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: Ripk1 Interacts With Various Proteins Such As Ciaps Andmentioning

confidence: 66%

Section: Ripk1 Interacts With Various Proteins Such As Ciaps Andmentioning

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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“…However, the role of caspase 8 is complex and context dependent as the causative agent of plague Yersinia pestis and its outer protein YopJ employs caspase 8, RIP1 and RIP3 to trigger cell death and caspase 1 activation. 123,124 Interestingly, another study demonstrated that pharmacological or genetic depletion of the cIAP proteins in macrophages, in conjunction with TLR stimulation, resulted in augmented processing of pro-IL-1b into its mature form. 125 The processing of IL-1b was driven by two independent pathways involving NLRP3/caspase 1 and caspase 8.…”

Section: Rip Kinases and The Inflammasomementioning

confidence: 99%

RIP kinases: key decision makers in cell death and innate immunity

et al. 2014

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“…However, Yersinia also inhibits inflammasome activation through the activities of YopK and YopM (36,38,39). Recent studies have revealed that YopJ can cooperate with YopM in activated macrophages to limit inflammasome activation (78,81), although YopJ blockade of NF-B and MAPK signaling triggers the activation of caspase-8 and caspase-1 in naive macrophages (82,83).…”

Section: Discussionmentioning

confidence: 99%

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

et al. 2017

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Gram-negative bacterial pathogens utilize virulence-associated secretion systems to inject, or translocate, effector proteins into host cells to manipulate cellular processes and promote bacterial replication. However, translocated bacterial products are sensed by nucleotide binding domain and leucine-rich repeat-containing proteins (NLRs), which trigger the formation of a multiprotein complex called the inflammasome, leading to secretion of interleukin-1 (IL-1) family cytokines, pyroptosis, and control of pathogen replication. Pathogenic Yersinia bacteria inject effector proteins termed Yops, as well as pore-forming proteins that comprise the translocon itself, into target cells. The Yersinia translocation regulatory protein YopK promotes bacterial virulence by limiting hyperinjection of the translocon proteins YopD and YopB into cells, thereby limiting cellular detection of Yersinia virulence activity. How hyperinjection of translocon proteins leads to inflammasome activation is currently unknown. We found that translocated YopB and YopD colocalized with the late endosomal/lysosomal protein LAMP1 and that the frequency of YopD and LAMP1 association correlated with the level of caspase-1 activation in individual cells. We also observed colocalization between YopD and Galectin-3, an indicator of endosomal membrane damage. Intriguingly, YopK limited the colocalization of Galectin-3 with YopD, suggesting that YopK limits the induction or sensing of endosomal membrane damage by components of the type III secretion system (T3SS) translocon. Furthermore, guanylate binding proteins (GBPs) encoded on chromosome 3 (Gbp Chr3 ), which respond to pathogen-induced damage or alteration of host membranes, were necessary for inflammasome activation in response to hyperinjected YopB/-D. Our findings indicate that lysosomal damage by Yersinia translocon proteins promotes inflammasome activation and implicate GBPs as key regulators of this process.

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Caspase-8 mediates caspase-1 processing and innate immune defense in response to bacterial blockade of NF-κB and MAPK signaling

Cited by 222 publications

References 43 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

RIP kinases: key decision makers in cell death and innate immunity

Guanylate Binding Proteins Regulate Inflammasome Activation in Response to Hyperinjected Yersinia Translocon Components

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