scholarly journals Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

2020 ◽  
Author(s):  
Anna Negroni ◽  
Eleonora Colantoni ◽  
Salvatore Cucchiara ◽  
Laura Stronati
Keyword(s):  
Cell Death ◽  
Intestinal Epithelium ◽  
Inflammatory Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Kinase Domain ◽  
Interacting Protein ◽  
New Concepts ◽  
Independent Form ◽  
Cellular Turnover

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

scholarly journals Necroptosis in Intestinal Inflammation and Cancer: New Concepts and Therapeutic Perspectives

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1431
Author(s):  
Anna Negroni ◽  
Eleonora Colantoni ◽  
Salvatore Cucchiara ◽  
Laura Stronati
Keyword(s):  
Cell Death ◽  
Intestinal Epithelium ◽  
Therapeutic Strategy ◽  
Molecular Mechanisms ◽  
Inflammatory Cell ◽  
Intestinal Inflammation ◽  
Kinase Domain ◽  
Interacting Protein ◽  
New Concepts ◽  
Cellular Turnover

Necroptosis is a caspases-independent programmed cell death displaying intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development such tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis plays a role in many disease conditions and inhibiting necroptosis is currently considered a promising therapeutic strategy. In this review, we focus on the molecular mechanisms of necroptosis as well as its involvement in human diseases. We also discuss the present developing therapies that target necroptosis machinery.

scholarly journals MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis

2017 ◽  
Vol 114 (36) ◽  
pp. E7450-E7459 ◽  
Author(s):  
Shuzhen Liu ◽  
Hua Liu ◽  
Andrea Johnston ◽  
Sarah Hanna-Addams ◽  
Eduardo Reynoso ◽  
...  
Keyword(s):  
Cell Death ◽  
Disulfide Bond ◽  
Kinase Domain ◽  
Proteinase K ◽  
Interacting Protein ◽  
Tnf Α ◽  
Mouse Cells ◽  
Red Dye ◽  
Necessary And Sufficient ◽  
Human And Mouse

Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α–induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.

scholarly journals The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils

2018 ◽  
Vol 11 (546) ◽  
pp. eaao1716 ◽  
Author(s):  
Akshay A. D’Cruz ◽  
Mary Speir ◽  
Meghan Bliss-Moreau ◽  
Sylvia Dietrich ◽  
Shu Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Domain ◽  
Neutrophil Extracellular Trap ◽  
Human Neutrophils ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Dependent Activity ◽  
Mrsa Infection ◽  
Death Effector ◽  
Net Release

Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain–like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase–independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. This process was coordinated by receptor-interacting protein kinase-1 (RIPK1), which activated the caspase-8–dependent apoptotic or RIPK3/MLKL-dependent necroptotic death of mouse and human neutrophils. Genetic deficiency of RIPK3 and MLKL prevented NET formation but did not prevent cell death, which was because of residual caspase-8–dependent activity. Peptidylarginine deiminase 4 (PAD4) was activated downstream of RIPK1/RIPK3/MLKL and was required for maximal histone hypercitrullination and NET extrusion. This work defines a distinct signaling network that activates PAD4-dependent NET release for the control of methicillin-resistant Staphylococcus aureus (MRSA) infection.

scholarly journals Necroptosis in Cholangiocarcinoma

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 982
Author(s):  
Samantha Sarcognato ◽  
Iris E. M. de Jong ◽  
Luca Fabris ◽  
Massimiliano Cadamuro ◽  
Maria Guido
Keyword(s):  
Cell Death ◽  
Current Knowledge ◽  
Kinase Domain ◽  
Alternative Mode ◽  
Interacting Protein ◽  
Regulated Cell Death ◽  
Anti Cancer ◽  
Regulatory Complex ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Necroptosis is a type of regulated cell death that is increasingly being recognized as a relevant pathway in different pathological conditions. Necroptosis can occur in response to multiple stimuli, is triggered by the activation of death receptors, and is regulated by receptor-interacting protein kinases 1 and 3 and mixed-lineage kinase domain-like, which form a regulatory complex called the necrosome. Accumulating evidence suggests that necroptosis plays a complex role in cancer, which is likely context-dependent and can vary among different types of neoplasms. Necroptosis serves as an alternative mode of programmed cell death overcoming apoptosis and, as a pro-inflammatory death type, it may inhibit tumor progression by releasing damage-associated molecular patterns to elicit robust cross-priming of anti-tumor CD8+ T cells. The development of therapeutic strategies triggering necroptosis shows great potential for anti-cancer therapy. In this review, we summarize the current knowledge on necroptosis and its role in liver biliary neoplasms, underlying the potential of targeting necroptosis components for cancer treatment.

scholarly journals Current translational potential and underlying molecular mechanisms of necroptosis

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Tamás Molnár ◽  
Anett Mázló ◽  
Vera Tslaf ◽  
Attila Gábor Szöllősi ◽  
Gabriella Emri ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Immune Surveillance ◽  
Kinase Domain ◽  
Tumor Formation

Abstract Cell death has a fundamental impact on the evolution of degenerative disorders, autoimmune processes, inflammatory diseases, tumor formation and immune surveillance. Over the past couple of decades extensive studies have uncovered novel cell death pathways, which are independent of apoptosis. Among these is necroptosis, a tightly regulated, inflammatory form of cell death. Necroptosis contribute to the pathogenesis of many diseases and in this review, we will focus exclusively on necroptosis in humans. Necroptosis is considered a backup mechanism of apoptosis, but the in vivo appearance of necroptosis indicates that both caspase-mediated and caspase-independent mechanisms control necroptosis. Necroptosis is regulated on multiple levels, from the transcription, to the stability and posttranslational modifications of the necrosome components, to the availability of molecular interaction partners and the localization of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL). Accordingly, we classified the role of more than seventy molecules in necroptotic signaling based on consistent in vitro or in vivo evidence to understand the molecular background of necroptosis and to find opportunities where regulating the intensity and the modality of cell death could be exploited in clinical interventions. Necroptosis specific inhibitors are under development, but >20 drugs, already used in the treatment of various diseases, have the potential to regulate necroptosis. By listing necroptosis-modulated human diseases and cataloging the currently available drug-repertoire to modify necroptosis intensity, we hope to kick-start approaches with immediate translational potential. We also indicate where necroptosis regulating capacity should be considered in the current applications of these drugs.

scholarly journals The novel cyclophilin-D-interacting protein FASTKD1 protects cells against oxidative stress-induced cell death

2019 ◽  
Vol 317 (3) ◽  
pp. C584-C599
Author(s):  
Kurt D. Marshall ◽  
Paula J. Klutho ◽  
Lihui Song ◽  
Maike Krenz ◽  
Christopher P. Baines
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Kinase Domain ◽  
Protective Role ◽  
Mitochondrial Morphology ◽  
Cyclophilin D ◽  
Interacting Protein ◽  
Mitochondrial Homeostasis

Opening of the mitochondrial permeability transition (MPT) pore leads to necrotic cell death. Excluding cyclophilin D (CypD), the makeup of the MPT pore remains conjecture. The purpose of these experiments was to identify novel MPT modulators by analyzing proteins that associate with CypD. We identified Fas-activated serine/threonine phosphoprotein kinase domain-containing protein 1 (FASTKD1) as a novel CypD interactor. Overexpression of FASTKD1 protected mouse embryonic fibroblasts (MEFs) against oxidative stress-induced reactive oxygen species (ROS) production and cell death, whereas depletion of FASTKD1 sensitized them. However, manipulation of FASTKD1 levels had no effect on MPT responsiveness, Ca2+-induced cell death, or antioxidant capacity. Moreover, elevated FASTKD1 levels still protected against oxidative stress in CypD-deficient MEFs. FASTKD1 overexpression decreased Complex-I-dependent respiration and ΔΨm in MEFs, effects that were abrogated in CypD-null cells. Additionally, overexpression of FASTKD1 in MEFs induced mitochondrial fragmentation independent of CypD, activation of Drp1, and inhibition of autophagy/mitophagy, whereas knockdown of FASTKD1 had the opposite effect. Manipulation of FASTKD1 expression also modified oxidative stress-induced caspase-3 cleavage yet did not alter apoptotic death. Finally, the effects of FASTKD1 overexpression on oxidative stress-induced cell death and mitochondrial morphology were recapitulated in cultured cardiac myocytes. Together, these data indicate that FASTKD1 supports mitochondrial homeostasis and plays a critical protective role against oxidant-induced death.

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 Oligomerization-driven MLKL ubiquitylation antagonises necroptosis

2021 ◽  
Author(s):  
Zikou Liu ◽  
Laura Francesca Dagley ◽  
Kristy Lynn Shield-Artin ◽  
Samuel Nicholas Young ◽  
Aleksandra Bankovacki ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Protein Kinase ◽  
Kinase Domain ◽  
Membrane Disruption ◽  
Fusion Strategy ◽  
Mixed Lineage Kinase ◽  
Independent Form ◽  
Lysine Residues ◽  
Kinetic Regulation

Mixed lineage kinase domain-like (MLKL) is the executioner in the caspase-independent form of programmed cell death called necroptosis. Receptor Interacting serine/threonine Protein Kinase 3 (RIPK3) phosphorylates MLKL, triggering MLKL oligomerization, membrane translocation and membrane disruption. MLKL also undergoes ubiquitylation during necroptosis, yet neither the mechanism nor significance of this event have been demonstrated. Here we show that necroptosis-specific, multi-mono-ubiquitylation of MLKL occurs following its activation and oligomerization. Ubiquitylated MLKL accumulates in a digitonin insoluble cell fraction comprising plasma/organellar membranes and protein aggregates. This ubiquitylated form is diminished by a plasma membrane located deubiquitylating enzyme. MLKL is ubiquitylated on at least 4 separate lysine residues once oligomerized, and this correlates with proteasome- and lysosome- dependent turnover. Using a MLKL-DUB fusion strategy, we show that constitutive removal of ubiquitin from MLKL licenses MLKL auto-activity independent of necroptosis signalling in mouse and human cells. Therefore, besides its role in the kinetic regulation of MLKL-induced death following an exogenous necroptotic stimulus, ubiquitylation also contributes to the restraint of basal levels of activated MLKL to avoid errant cell death.

scholarly journals Human RIPK3 maintains MLKL in an inactive conformation prior to cell death by necroptosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yanxiang Meng ◽  
Katherine A. Davies ◽  
Cheree Fitzgibbon ◽  
Samuel N. Young ◽  
Sarah E. Garnish ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Defense ◽  
Inflammatory Diseases ◽  
Kinase Domain ◽  
Human Cells ◽  
Complex Assembly ◽  
Inactive Conformation ◽  
Upstream Regulator ◽  
Widespread Interest ◽  
Terminal Effector

AbstractThe ancestral origins of the lytic cell death mode, necroptosis, lie in host defense. However, the dysregulation of necroptosis in inflammatory diseases has led to widespread interest in targeting the pathway therapeutically. This mode of cell death is executed by the terminal effector, the MLKL pseudokinase, which is licensed to kill following phosphorylation by its upstream regulator, RIPK3 kinase. The precise molecular details underlying MLKL activation are still emerging and, intriguingly, appear to mechanistically-diverge between species. Here, we report the structure of the human RIPK3 kinase domain alone and in complex with the MLKL pseudokinase. These structures reveal how human RIPK3 structurally differs from its mouse counterpart, and how human RIPK3 maintains MLKL in an inactive conformation prior to induction of necroptosis. Residues within the RIPK3:MLKL C-lobe interface are crucial to complex assembly and necroptotic signaling in human cells, thereby rationalizing the strict species specificity governing RIPK3 activation of MLKL.

scholarly journals The lncRNA H19-Derived MicroRNA-675 Promotes Liver Necroptosis by Targeting FADD

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 411
Author(s):  
Rona Harari-Steinfeld ◽  
Maytal Gefen ◽  
Alina Simerzin ◽  
Elina Zorde-Khvalevsky ◽  
Mila Rivkin ◽  
...  
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Specific Inhibitor ◽  
Kinase Domain ◽  
Tumor Promoter ◽  
Death Domain ◽  
Liver Inflammation ◽  
Interacting Protein ◽  
Important Regulator ◽  
Cell Death Signaling

The H19-derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), a mediator of apoptotic cell death signaling, is downregulated by miR-675 and a negative correlation exists between miR-675 and FADD expression in mouse models of HCC (p = 0.014) as well as in human samples (p = 0.017). We demonstrate in a mouse model of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift from apoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD by miR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC.

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