scholarly journals Receptor-Interacting Protein Kinases 1 and 3, and Mixed Lineage Kinase Domain-Like Protein Are Activated by Sublytic Complement and Participate in Complement-Dependent Cytotoxicity

2018 ◽  
Vol 9 ◽  
Author(s):  
Michal Lusthaus ◽  
Niv Mazkereth ◽  
Natalie Donin ◽  
Zvi Fishelson
Keyword(s):  
Protein Kinases ◽  
Kinase Domain ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Complement Dependent Cytotoxicity

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 The molecular mechanisms of MLKL-dependent and MLKL-independent necrosis

2020 ◽  
Author(s):  
Lu Li ◽  
An Tong ◽  
Qiangsheng Zhang ◽  
Yuquan Wei ◽  
Xiawei Wei
Keyword(s):  
Molecular Mechanisms ◽  
Death Receptor ◽  
Kinase Domain ◽  
External Stress ◽  
Programmed Necrosis ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Caspase Inhibition ◽  
Regulated Necrosis ◽  
Receptor Family

Abstract Necrosis, a type of unwanted and passive cell demise, usually occurs under the excessive external stress and is considered to be unregulated. However, under some special conditions such as caspase inhibition, necrosis is regulable in a well-orchestrated way. The term ‘regulated necrosis’ has been proposed to describe such programmed necrosis. Recently, several forms of necrosis, including necroptosis, pyroptosis, ferroptosis, parthanatos, oxytosis, NETosis, and Na+/K+-ATPase-mediated necrosis, have been identified, and some crucial regulators governing regulated necrosis have also been discovered. Mixed lineage kinase domain-like pseudokinase (MLKL), a core regulator in necroptosis, acts as an executioner in response to ligands of death receptor family. Its activation requires the receptor-interacting protein kinases, RIP1 and RIP3. However, MLKL is only involved in necroptosis, that is, MLKL is dispensable for necrosis. Therefore, this review is aimed at summarizing the molecular mechanisms of MLKL-dependent and MLKL-independent necrosis.

scholarly journals Diverse Sequence Determinants Control Human and Mouse Receptor Interacting Protein 3 (RIP3) and Mixed Lineage Kinase domain-Like (MLKL) Interaction in Necroptotic Signaling

2013 ◽  
Vol 288 (23) ◽  
pp. 16247-16261 ◽  
Author(s):  
Wanze Chen ◽  
Zhenru Zhou ◽  
Lisheng Li ◽  
Chuan-Qi Zhong ◽  
Xinru Zheng ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Phosphorylation Sites ◽  
Flanking Sequence ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Signaling Complex ◽  
Evolutionarily Conserved ◽  
Mouse Cells ◽  
Human And Mouse

Receptor interacting protein 3 (RIP3) is a protein kinase essential for TNF-induced necroptosis. Phosphorylation on Ser-227 in human RIP3 (hRIP3) is required for its interaction with human mixed lineage kinase domain-like (MLKL) in the necrosome, a signaling complex induced by TNF stimulation. RIP1 and RIP3 mediate necrosome aggregation leading to the formation of amyloid-like signaling complexes. We found that TNF induces Thr-231 and Ser-232 phosphorylation in mouse RIP3 (mRIP3) and this phosphorylation is required for mRIP3 to interact with mMLKL. Ser-232 in mRIP3 corresponds to Ser-227 in hRIP3, whereas Thr-231 is not conserved in hRIP3. Although the RIP3-MLKL interaction is required for necroptosis in both human and mouse cells, hRIP3 does not interact with mMLKL and mRIP3 cannot bind to hMLKL. The species specificity of the RIP3-MLKL interaction is primarily determined by the sequence differences in the phosphorylation sites and the flanking sequence around the phosphorylation sites in hRIP3 and mRIP3. It appears that the RIP3-MLKL interaction has been selected as an evolutionarily conserved mechanism in mediating necroptosis signaling despite that differing structural and mechanistic bases for this interaction emerged simultaneously in different organisms. In addition, we further revealed that the interaction of RIP3 with MLKL prevented massive abnormal RIP3 aggregation, and therefore should be crucial for formation of the amyloid signaling complex of necrosomes. We also found that the interaction between RIP3 and MLKL is required for the translocation of necrosomes to mitochondria-associated membranes. Our data demonstrate the importance of the RIP3-MLKL interaction in the formation of functional necrosomes and suggest that translocation of necrosomes to mitochondria-associated membranes is essential for necroptosis signaling.

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 CK1α, CK1δ, and CK1ε are necrosome components which phosphorylate serine 227 of human RIPK3 to activate necroptosis

2020 ◽  
Vol 117 (4) ◽  
pp. 1962-1970 ◽  
Author(s):  
Sarah Hanna-Addams ◽  
Shuzhen Liu ◽  
Hua Liu ◽  
She Chen ◽  
Zhigao Wang
Keyword(s):  
Kinase Activity ◽  
Kinase Domain ◽  
Necrotic Cell ◽  
Interacting Protein ◽  
Casein Kinase 1 ◽  
Mixed Lineage Kinase ◽  
Recognition Motif ◽  
Cell Death Pathway

Necroptosis is a regulated necrotic cell death pathway, mediated by a supermolecular complex called the necrosome, which contains receptor-interacting protein kinase 1 and 3 (RIPK1, RIPK3) and mixed-lineage kinase domain-like protein (MLKL). Phosphorylation of human RIPK3 at serine 227 (S227) has been shown to be required for downstream MLKL binding and necroptosis progression. Tandem immunoprecipitation of RIPK3 reveals that casein kinase 1 (CK1) family proteins associate with the necrosome upon necroptosis induction, and this interaction depends on the kinase activity of RIPK3. In addition, CK1 proteins colocalize with RIPK3 puncta during necroptosis. Importantly, CK1 proteins directly phosphorylate RIPK3 at S227 in vitro and in vivo. Loss of CK1 proteins abolishes S227 phosphorylation and blocks necroptosis. Furthermore, a RIPK3 mutant with mutations in the CK1 recognition motif fails to be phosphorylated at S227, does not bind or phosphorylate MLKL, and is unable to activate necroptosis. These results strongly suggest that CK1 proteins are necrosome components which are responsible for RIPK3-S227 phosphorylation.

scholarly journals O-GlcNAc transferase suppresses necroptosis and liver fibrosis

2019 ◽  
Author(s):  
Bichen Zhang ◽  
Min-Dian Li ◽  
Ruonan Yin ◽  
Yuyang Liu ◽  
Yunfan Yang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Diseases ◽  
Genetic Model ◽  
Kinase Domain ◽  
Early Age ◽  
Chronic Liver Diseases ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Elevated Protein ◽  
Glcnac Transferase

AbstractOver a billion people suffer from chronic liver diseases worldwide, which often leads to fibrosis and then cirrhosis. Treatments for fibrosis remain experimental, in part because no unifying mechanism has been identified that initiates liver fibrosis. Here we report that O-linked β-N-acetylglucosamine (O-GlcNAc) modification protects against hepatocyte necroptosis and initiation of liver fibrosis. Decreased O-GlcNAc levels were seen in patients with liver cirrhosis and in mice with ethanol-induced liver injury. Liver-specific O-GlcNAc transferase (OGT) knockout (OGT-LKO) mice exhibited ballooning degeneration and elevated circulating alanine aminotransferase (ALT) levels at an early age and progressed to liver fibrosis and portal inflammation by 10 weeks of age. OGT-deficient hepatocytes underwent excessive necroptosis and exhibited elevated protein expression levels of receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like (MLKL), which are key mediators of necroptosis. Furthermore, glycosylation of RIPK3 by OGT reduced RIPK3 protein stability. Taken together, these findings identify OGT as a key suppressor of hepatocyte necroptosis and OGT-LKO mice may serve as an effective spontaneous genetic model of liver fibrosis.

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 Uncovering human mixed lineage kinase domain-like activation in necroptosis

2019 ◽  
Vol 11 (21) ◽  
pp. 2831-2844
Author(s):  
Cristina D Guibao ◽  
Katherine Petrinjak ◽  
Tudor Moldoveanu
Keyword(s):  
Plasma Membrane ◽  
Protein Kinase ◽  
Recent Progress ◽  
Inositol Phosphate ◽  
Kinase Domain ◽  
Structural Studies ◽  
Interacting Protein ◽  
Mixed Lineage Kinase ◽  
Membrane Rupture ◽  
Essential Components

MLKL and its obligate upstream receptor interacting protein kinase 3 are essential components of necroptosis. It is well established that MLKL is the executioner of plasma membrane rupture in necroptosis. In healthy cells MLKL is dormant. Several dormant configurations have emerged from high-resolution structural studies revealing distinct mechanisms of MLKL autoinhibition in mammals. MLKL is activated through the concerted actions of receptor interacting protein kinase 3, which phosphorylates MLKL, and, in the case of the human pathway, inositol phosphate (IP) metabolites synthesized by the IP kinases of the IP metabolic pathway. Here, we highlight recent progress toward understanding the mechanisms of regulation of human MLKL, and survey the latest opportunities for targeting MLKL in pathophysiology.

Expression of Receptor Interacting Protein Kinase-3 and Mixed Lineage Kinase Domain-Like Protein in Patients with COPD

2019 ◽  
Author(s):  
F. Verhamme ◽  
H.P. Van Eeckhoutte ◽  
T. Buyle-Huybrecht ◽  
G.G. Brusselle ◽  
P. Vandenabeele ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Domain ◽  
Interacting Protein ◽  
Mixed Lineage Kinase
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