scholarly journals Regulation of Necroptosis by Phospholipids and Sphingolipids

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 627 ◽  
Author(s):  
Xuewei Zhang ◽  
Masaya Matsuda ◽  
Nobuo Yaegashi ◽  
Takeshi Nabe ◽  
Kazuyuki Kitatani
Keyword(s):  
Cell Death ◽  
Protein Kinases ◽  
Kinase Domain ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Cell Death Pathways ◽  
Regulated Cell Death

Several non-apoptotic regulated cell death pathways have been recently reported. Necroptosis, a form of necrotic-regulated cell death, is characterized by the involvement of receptor-interacting protein kinases and/or the pore-forming mixed lineage kinase domain-like protein. Recent evidence suggests a key role for lipidic molecules in the regulation of necroptosis. The purpose of this mini-review is to outline the regulation of necroptosis by sphingolipids and phospholipids.

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 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.

Location, location, location: A compartmentalized view of TNF-induced necroptotic signaling

2021 ◽  
Vol 14 (668) ◽  
pp. eabc6178
Author(s):  
André L. Samson ◽  
Sarah E. Garnish ◽  
Joanne M. Hildebrand ◽  
James M. Murphy
Keyword(s):  
Cell Death ◽  
Protein Kinases ◽  
Host Defense ◽  
Kinase Domain ◽  
Dependent Manner ◽  
Cell Type ◽  
Mixed Lineage Kinase ◽  
Cell Death Pathway ◽  
Subcellular Compartmentalization ◽  
High Degree

Necroptosis is a lytic, proinflammatory cell death pathway, which has been implicated in host defense and, when dysregulated, the pathology of many human diseases. The central mediators of this pathway are the receptor-interacting serine/threonine protein kinases RIPK1 and RIPK3 and the terminal executioner, the pseudokinase mixed lineage kinase domain–like (MLKL). Here, we review the chronology of signaling along the RIPK1-RIPK3-MLKL axis and highlight how the subcellular compartmentalization of signaling events controls the initiation and execution of necroptosis. We propose that a network of modulators surrounds the necroptotic signaling core and that this network, rather than acting universally, tunes necroptosis in a context-, cell type–, and species-dependent manner. Such a high degree of mechanistic flexibility is likely an important property that helps necroptosis operate as a robust, emergency form of cell death.

scholarly journals Necroptosis in Pulmonary Diseases: A New Therapeutic Target

2021 ◽  
Vol 12 ◽  
Author(s):  
Lingling Wang ◽  
Ling Zhou ◽  
Yuhao Zhou ◽  
Lu Liu ◽  
Weiling Jiang ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membranes ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Kinase Domain ◽  
The Body ◽  
Interacting Protein ◽  
Membrane Rupture ◽  
Regulated Cell Death ◽  
Scientific Attention

In the past decades, apoptosis has been the most well-studied regulated cell death (RCD) that has essential functions in tissue homeostasis throughout life. However, a novel form of RCD called necroptosis, which requires receptor-interacting protein kinase-3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has recently been receiving increasing scientific attention. The phosphorylation of RIPK3 enables the recruitment and phosphorylation of MLKL, which oligomerizes and translocates to the plasma membranes, ultimately leading to plasma membrane rupture and cell death. Although apoptosis elicits no inflammatory responses, necroptosis triggers inflammation or causes an innate immune response to protect the body through the release of damage-associated molecular patterns (DAMPs). Increasing evidence now suggests that necroptosis is implicated in the pathogenesis of several human diseases such as systemic inflammation, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, neurological diseases, and cancer. This review summarizes the emerging insights of necroptosis and its contribution toward the pathogenesis of lung diseases.

scholarly journals Receptor Interacting Protein Kinases 1/3: The Potential Therapeutic Target for Cardiovascular Inflammatory Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Yiming Leng ◽  
Ying Zhang ◽  
Xinyu Li ◽  
Zeyu Wang ◽  
Quan Zhuang ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinases ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Myocardial Remodeling ◽  
Inflammatory Signaling ◽  
Potential Therapeutic Target ◽  
Interacting Protein ◽  
Cell Death Pathways ◽  
Abdominal Aortic

The receptor interacting protein kinases 1/3 (RIPK1/3) have emerged as the key mediators in cell death pathways and inflammatory signaling, whose ubiquitination, phosphorylation, and inhibition could regulate the necroptosis and apoptosis effectually. Recently, more and more studies show great interest in the mechanisms and the regulator of RIPK1/3-mediated inflammatory response and in the physiopathogenesis of cardiovascular diseases. The crosstalk of autophagy and necroptosis in cardiomyocyte death is a nonnegligible conversation of cell death. We elaborated on RIPK1/3-mediated necroptosis, pathways involved, the latest regulatory molecules and therapeutic targets in terms of ischemia reperfusion, myocardial remodeling, myocarditis, atherosclerosis, abdominal aortic aneurysm, and cardiovascular transplantation, etc.

scholarly journals Effects of prostaglandin F2α (PGF2α) on cell-death pathways in the bovine corpus luteum (CL)

2019 ◽  
Vol 15 (1) ◽  
Author(s):  
Agnieszka Walentyna Jonczyk ◽  
Katarzyna Karolina Piotrowska-Tomala ◽  
Dariusz Jan Skarzynski
Keyword(s):  
Cell Death ◽  
Corpus Luteum ◽  
Early Stage ◽  
Prostaglandin F2α ◽  
B Cell Lymphoma ◽  
Kinase Domain ◽  
Interacting Protein ◽  
Middle Stage ◽  
Cell Death Pathways ◽  
Prostaglandin F

Abstract Background Prostaglandin F2α (PGF2α) may differentially affect viability of luteal cells by inducing either proliferation or cell death (via apoptosis or necroptosis). The diverse effects of PGF2α may depend on its local vs. systemic actions. In our study, we determined changes in expression of genes related to: (i) apoptosis: caspase (CASP) 3, CASP8, BCL2 associated X (BAX), B-cell lymphoma 2 (BCL2) and (ii) necroptosis: receptor-interacting protein kinase (RIPK) 1, RIPK3, cylindromatosis (CYLD), and mixed lineage kinase domain-like (MLKL) in the early and mid-stage corpus luteum (CL) that accompany local (intra-CL) vs. systemic (i.m.) analogue of PGF2α (aPGF2α) actions. Cows at day 4 (n = 24) or day 10 (n = 24) of the estrous cycle were treated by injections as follows: (1) systemic saline, (2) systemic aPGF2α (25 mg; Dinoprost), (3) local saline, (4) local aPGF2α (2.5 mg; Dinoprost). After 4 h, CLs were collected by ovariectomy. Expression levels of mRNA and protein were investigated by RT-q PCR, Western blotting and immunohistochemistry, respectively. Results We found that local and systemic administration of aPGF2α in the early-stage CL resulted in decreased expression of CASP3 (P < 0.01), but CASP8 mRNA expression was up-regulated (P < 0.05). However, the expression of CASP3 was up-regulated after local aPGF2α treatment in the middle-stage CL, whereas systemic aPGF2α administration increased both CASP3 and CASP8 expression (P < 0.01). Moreover, we observed that both local and systemic aPGF2α injections increased RIPK1, RIPK3 and MLKL expression in the middle-stage CL (P < 0.05) while CYLD expression was markedly higher after i.m. aPGF2α injections (P < 0.001). Moreover, we investigated the localization of necroptotic factors (RIPK1, RIPK3, CYLD and MLKL) in bovine CL tissue after local and systemic aPGF2α injections in the bovine CL. Conclusion Our results demonstrated for the first time that genes related to cell death pathways exhibit stage-specific responses to PGF2α administration depending on its local or systemic actions. Locally-acting PGF2α plays a luteoprotective role by inhibiting apoptosis and necroptosis in the early CL. Necroptosis is a potent mechanism responsible for structural CL regression during PGF2α-induced luteolysis in cattle.

scholarly journals Post-translational control of RIPK3 and MLKL mediated necroptotic cell death

F1000Research ◽  
2015 ◽  
Vol 4 ◽  
pp. 1297 ◽  
Author(s):  
James M. Murphy ◽  
James E. Vince
Keyword(s):  
Cell Death ◽  
Translational Control ◽  
Kinase Domain ◽  
Current Evidence ◽  
Deubiquitinating Enzymes ◽  
Critical Function ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Microbial Infections ◽  
Cell Death Mechanisms

Several programmed lytic and necrotic-like cell death mechanisms have now been uncovered, including the recently described receptor interacting protein kinase-3 (RIPK3)-mixed lineage kinase domain-like (MLKL)-dependent necroptosis pathway. Genetic experiments have shown that programmed necrosis, including necroptosis, can play a pivotal role in regulating host-resistance against microbial infections. Alternatively, excess or unwarranted necroptosis may be pathological in autoimmune and autoinflammatory diseases. This review highlights the recent advances in our understanding of the post-translational control of RIPK3-MLKL necroptotic signaling. We discuss the critical function of phosphorylation in the execution of necroptosis, and highlight the emerging regulatory roles for several ubiquitin ligases and deubiquitinating enzymes. Finally, based on current evidence, we discuss the potential mechanisms by which the essential, and possibly terminal, necroptotic effector, MLKL, triggers the disruption of cellular membranes to cause cell lysis.

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 evolution of regulated cell death pathways in animals and their evasion by pathogens

2022 ◽  
Vol 102 (1) ◽  
pp. 411-454
Author(s):  
Bart Tummers ◽  
Douglas R. Green
Keyword(s):  
Cell Death ◽  
Physiological Traits ◽  
Molecular Pathways ◽  
Host Pathogen Interactions ◽  
Cell Death Pathways ◽  
Regulated Cell Death ◽  
Host Pathogen ◽  
Animal Hosts

The coevolution of host-pathogen interactions underlies many human physiological traits associated with protection from or susceptibility to infections. Among the mechanisms that animals utilize to control infections are the regulated cell death pathways of pyroptosis, apoptosis, and necroptosis. Over the course of evolution these pathways have become intricate and complex, coevolving with microbes that infect animal hosts. Microbes, in turn, have evolved strategies to interfere with the pathways of regulated cell death to avoid eradication by the host. Here, we present an overview of the mechanisms of regulated cell death in Animalia and the strategies devised by pathogens to interfere with these processes. We review the molecular pathways of regulated cell death, their roles in infection, and how they are perturbed by viruses and bacteria, providing insights into the coevolution of host-pathogen interactions and cell death pathways.

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