scholarly journals ZBP1 induces inflammatory signaling via RIPK3 and promotes SARS-CoV-2-induced cytokine expression

2021 ◽  
Author(s):  
Ruoshi Peng ◽  
Xuan Wang-Kan ◽  
Manja Idorn ◽  
Felix Y Zhou ◽  
Susana L Orozco ◽  
...  
Keyword(s):  
Cell Death ◽  
Signaling Pathway ◽  
Kinase Activity ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Inflammatory Signaling ◽  
Antiviral Responses ◽  
Nucleic Acid Sensor ◽  
Activity Dependent

AbstractCOVID-19 caused by the SARS-CoV-2 virus remains a threat to global health. The disease severity is mediated by cell death and inflammation, which regulate both the antiviral and the pathological innate immune responses. ZBP1, an interferon-induced cytosolic nucleic acid sensor, facilitates antiviral responses via RIPK3. Although ZBP1-mediated cell death is widely described, whether and how it promotes inflammatory signaling is unclear. Here, we report a ZBP1-induced inflammatory signaling pathway that depends on ubiquitination and RIPK3’s scaffolding ability independently of cell death. In human cells, ZBP1 associates with RIPK1 and RIPK3 as well as ubiquitin ligases cIAP1 and LUBAC. RIPK1 and ZBP1 are ubiquitinated to promote TAK1- and IKK-mediated inflammatory signaling. Additionally, RIPK1 recruits the p43/41-caspase-8-p43-FLIP heterodimer to suppress RIPK3 kinase activity, which otherwise promotes inflammatory signaling in a kinase activity-dependent manner. Lastly, we show that ZBP1 contributes to SARS-CoV-2-induced cytokine production. Taken together, we describe a ZBP1-RIPK1-RIPK3-mediated inflammatory signaling pathway relayed by the scaffolding role of RIPKs and regulated by caspase-8. Our results suggest the ZBP1 pathway contributes to inflammation in response to SARS-CoV-2 infection.

scholarly journals ZBP1 promotes LPS-induced cell death and IL-1β release via RHIM-mediated interactions with RIPK1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hayley I. Muendlein ◽  
Wilson M. Connolly ◽  
Zoie Magri ◽  
Irina Smirnova ◽  
Vladimir Ilyukha ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Complex Formation ◽  
Complex I ◽  
Yersinia Pseudotuberculosis ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Inflammatory Signaling ◽  
Complex Ii ◽  
Dependent Model

AbstractInflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival. One example of this balance is the tightly regulated transition from TNFR1-associated pro-inflammatory complex I to pro-death complex II. By contrast, here we show that a TRIF-dependent complex containing FADD, RIPK1 and caspase-8 (that we have termed the TRIFosome) mediates cell death in response to Yersinia pseudotuberculosis and LPS. Furthermore, we show that constitutive binding between ZBP1 and RIPK1 is essential for the initiation of TRIFosome interactions, caspase-8-mediated cell death and inflammasome activation, thus positioning ZBP1 as an effector of cell death in the context of bacterial blockade of pro-inflammatory signaling. Additionally, our findings offer an alternative to the TNFR1-dependent model of complex II assembly, by demonstrating pro-death complex formation reliant on TRIF signaling.

Genetic Regulation of RIPK1 and Necroptosis

2021 ◽  
Vol 55 (1) ◽  
pp. 235-263
Author(s):  
Daichao Xu ◽  
Chengyu Zou ◽  
Junying Yuan
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Genetic Regulation ◽  
Caspase 8 ◽  
Inflammatory Signaling ◽  
Interacting Protein ◽  
Multiple Factors ◽  
Cell Death Pathways ◽  
Upstream Regulator ◽  
Multiple Cell

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.

scholarly journals Innate immune priming in the absence of TAK1 drives RIPK1 kinase activity–independent pyroptosis, apoptosis, necroptosis, and inflammatory disease

2019 ◽  
Vol 217 (3) ◽  
Author(s):  
R.K. Subbarao Malireddi ◽  
Prajwal Gurung ◽  
Sannula Kesavardhana ◽  
Parimal Samir ◽  
Amanda Burton ◽  
...  
Keyword(s):  
Cell Death ◽  
Severe Sepsis ◽  
Kinase Activity ◽  
Innate Immune ◽  
Caspase 8 ◽  
Inflammasome Activation ◽  
Unknown Mechanism ◽  
Immune Priming ◽  
Signaling Axis

RIPK1 kinase activity has been shown to be essential to driving pyroptosis, apoptosis, and necroptosis. However, here we show a kinase activity–independent role for RIPK1 in these processes using a model of TLR priming in a TAK1-deficient setting to mimic pathogen-induced priming and inhibition. TLR priming of TAK1-deficient macrophages triggered inflammasome activation, including the activation of caspase-8 and gasdermin D, and the recruitment of NLRP3 and ASC into a novel RIPK1 kinase activity–independent cell death complex to drive pyroptosis and apoptosis. Furthermore, we found fully functional RIPK1 kinase activity–independent necroptosis driven by the RIPK3–MLKL pathway in TAK1-deficient macrophages. In vivo, TAK1 inactivation resulted in RIPK3–caspase-8 signaling axis–driven myeloid proliferation and a severe sepsis-like syndrome. Overall, our study highlights a previously unknown mechanism for RIPK1 kinase activity–independent inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis) that could be targeted for treatment of TAK1-associated myeloid proliferation and sepsis.

scholarly journals Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways

2017 ◽  
Vol 114 (13) ◽  
pp. E2786-E2795 ◽  
Author(s):  
Lisa P. Daley-Bauer ◽  
Linda Roback ◽  
Lynsey N. Crosby ◽  
A. Louise McCormick ◽  
Yanjun Feng ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Double Mutant ◽  
Kinase Domain ◽  
Murine Cytomegalovirus ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Antiviral Responses ◽  
Cell Death Pathways ◽  
Infected Cells

The complex interplay between caspase-8 and receptor-interacting protein (RIP) kinase RIP 3 (RIPK3) driving extrinsic apoptosis and necroptosis is not fully understood. Murine cytomegalovirus triggers both apoptosis and necroptosis in infected cells; however, encoded inhibitors of caspase-8 activity (M36) and RIP3 signaling (M45) suppress these antiviral responses. Here, we report that this virus activates caspase-8 in macrophages to trigger apoptosis that gives rise to secondary necroptosis. Infection with double-mutant ΔM36/M45mutRHIM virus reveals a signaling pattern in which caspase-8 activates caspase-3 to drive apoptosis with subsequent RIP3-dependent activation of mixed lineage kinase domain-like (MLKL) leading to necroptosis. This combined cell death signaling is highly inflammatory, greater than either apoptosis induced by ΔM36 or necroptosis induced by M45mutRHIM virus. IL-6 production by macrophages is dramatically increased during double-mutant virus infection and correlates with faster antiviral responses in the host. Collaboratively, M36 and M45 target caspase-8 and RIP3 pathways together to suppress this proinflammatory cell death. This study reveals the effect of antiviral programmed cell death pathways on inflammation, shows that caspase-8 activation may go hand-in-hand with necroptosis in macrophages, and revises current understanding of independent and collaborative functions of M36 and M45 in blocking apoptotic and necroptotic cell death responses.

scholarly journals Caspase-8 is activated by cathepsin D initiating neutrophil apoptosis during the resolution of inflammation

2008 ◽  
Vol 205 (3) ◽  
pp. 685-698 ◽  
Author(s):  
Sébastien Conus ◽  
Remo Perozzo ◽  
Thomas Reinheckel ◽  
Christoph Peters ◽  
Leonardo Scapozza ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cathepsin D ◽  
Defense Mechanisms ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Caspase 8 ◽  
Neutrophil Apoptosis ◽  
Dependent Manner ◽  
Innate Immune Responses ◽  
Inflammatory Conditions

In the resolution of inflammatory responses, neutrophils rapidly undergo apoptosis. We describe a new proapoptotic pathway in which cathepsin D directly activates caspase-8. Cathepsin D is released from azurophilic granules in neutrophils in a caspase-independent but reactive oxygen species–dependent manner. Under inflammatory conditions, the translocation of cathepsin D in the cytosol is blocked. Pharmacological or genetic inhibition of cathepsin D resulted in delayed caspase activation and reduced neutrophil apoptosis. Cathepsin D deficiency or lack of its translocation in the cytosol prolongs innate immune responses in experimental bacterial infection and in septic shock. Thus, we identified a new function of azurophilic granules that is in addition to their role in bacterial defense mechanisms: to regulate the life span of neutrophils and, therefore, the duration of innate immune responses through the release of cathepsin D.

scholarly journals Enhanced RIPK3 kinase activity-dependent lytic cell death in M1 but not M2 macrophages

2021 ◽  
Vol 129 ◽  
pp. 86-93
Author(s):  
Qin Hao ◽  
Suman Kundu ◽  
Joshua Kleam ◽  
Zhizhuang Joe Zhao ◽  
Steven Idell ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Activity ◽  
M2 Macrophages ◽  
Activity Dependent

Compressive Force Induces Osteoblast Apoptosis via Caspase-8

2006 ◽  
Vol 85 (3) ◽  
pp. 240-244 ◽  
Author(s):  
Y. Goga ◽  
M. Chiba ◽  
Y. Shimizu ◽  
H. Mitani
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Tooth Movement ◽  
Orthodontic Tooth Movement ◽  
Compressive Force ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Caspase 9 ◽  
Osteoblast Apoptosis

Periodontal remodeling during orthodontic tooth movement is a result of mechanical stresses. The application of excessive orthodontic force induces cell death. However, the nature of compressive force-induced cell death is unclear. We examined whether the in vitro application of continuous compressive force would induce apoptosis in human osteoblast-like cells (MG-63 cells), and investigated the mechanism by which apoptosis was initiated. The cells became aligned irregularly, and cell viability decreased, indicating that the compressive force caused cell death. According to the TUNEL analysis, the number of apoptotic cells increased significantly in a time-and force-dependent manner. Caspase-3 activity increased with the magnitude of the compressive force, and this effect was reduced significantly by a caspase-8 inhibitor, whereas a caspase-9 inhibitor had no such effect. We conclude that the in vitro application of compressive force can induce apoptosis in MG-63 cells through the activation of caspase-3 via the caspase-8 signaling cascade.

scholarly journals Caspase-8 and RIP kinases regulate bacteria-induced innate immune responses and cell death

2014 ◽  
Vol 111 (20) ◽  
pp. 7391-7396 ◽  
Author(s):  
D. Weng ◽  
R. Marty-Roix ◽  
S. Ganesan ◽  
M. K. Proulx ◽  
G. I. Vladimer ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Innate Immune ◽  
Caspase 8 ◽  
Innate Immune Responses

scholarly journals MIND bomb 2 prevents RIPK1 kinase activity-dependent and -independent apoptosis through ubiquitylation of cFLIPL

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Osamu Nakabayashi ◽  
Hirotaka Takahashi ◽  
Kenta Moriwaki ◽  
Sachiko Komazawa-Sakon ◽  
Fumiaki Ohtake ◽  
...  
Keyword(s):  
Complex I ◽  
Kinase Activity ◽  
Notch Signalling ◽  
Caspase 8 ◽  
Inhibitory Protein ◽  
Interacting Protein ◽  
Polyubiquitin Chains ◽  
Long Form ◽  
Induced Apoptosis ◽  
Activity Dependent

AbstractMind bomb 2 (MIB2) is an E3 ligase involved in Notch signalling and attenuates TNF-induced apoptosis through ubiquitylation of receptor-interacting protein kinase 1 (RIPK1) and cylindromatosis. Here we show that MIB2 bound and conjugated K48– and K63–linked polyubiquitin chains to a long-form of cellular FLICE-inhibitory protein (cFLIPL), a catalytically inactive homologue of caspase 8. Deletion of MIB2 did not impair the TNF-induced complex I formation that mediates NF-κB activation but significantly enhanced formation of cytosolic death-inducing signalling complex II. TNF-induced RIPK1 Ser166 phosphorylation, a hallmark of RIPK1 death-inducing activity, was enhanced in MIB2 knockout cells, as was RIPK1 kinase activity-dependent and -independent apoptosis. Moreover, RIPK1 kinase activity-independent apoptosis was induced in cells expressing cFLIPL mutants lacking MIB2-dependent ubiquitylation. Together, these results suggest that MIB2 suppresses both RIPK1 kinase activity-dependent and -independent apoptosis, through suppression of RIPK1 kinase activity and ubiquitylation of cFLIPL, respectively.

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