scholarly journals Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death

Cell Research ◽  
2013 ◽  
Vol 24 (1) ◽  
pp. 105-121 ◽  
Author(s):  
Xin Chen ◽  
Wenjuan Li ◽  
Junming Ren ◽  
Deli Huang ◽  
Wan-ting He ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Kinase Domain ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Mixed Lineage Kinase

scholarly journals Elisidepsin Interacts Directly with Glycosylceramides in the Plasma Membrane of Tumor Cells to Induce Necrotic Cell Death

PLoS ONE ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. e0140782 ◽  
Author(s):  
José Manuel Molina-Guijarro ◽  
Carolina García ◽  
Álvaro Macías ◽  
Luis Francisco García-Fernández ◽  
Cristina Moreno ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Tumor Cells ◽  
Necrotic Cell Death ◽  
Necrotic Cell

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 Irvalec Inserts Into the Plasma Membrane Causing Rapid Loss of Integrity and Necrotic Cell Death in Tumor Cells

2012 ◽  
Vol 102 (3) ◽  
pp. 65a-66a
Author(s):  
Alvaro Macias ◽  
Jose M. Molina-Guijarro ◽  
Miren David ◽  
Cristina Moreno ◽  
de la Cruz Alicia ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Tumor Cells ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Rapid Loss

scholarly journals Irvalec Inserts into the Plasma Membrane Causing Rapid Loss of Integrity and Necrotic Cell Death in Tumor Cells

PLoS ONE ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. e19042 ◽  
Author(s):  
José M. Molina-Guijarro ◽  
Álvaro Macías ◽  
Carolina García ◽  
Eva Muñoz ◽  
Luis F. García-Fernández ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Tumor Cells ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Rapid Loss

Monocytic cell necrosis is mediated by potassium depletion and caspase-like proteases

1999 ◽  
Vol 276 (3) ◽  
pp. C717-C724 ◽  
Author(s):  
Michel Warny ◽  
Ciarán P. Kelly
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Cysteine Proteases ◽  
Morphological Features ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Monocytic Cell ◽  
Mitochondrial Permeability

Apoptosis is a physiological cell death that culminates in mitochondrial permeability transition and the activation of caspases, a family of cysteine proteases. Necrosis, in contrast, is a pathological cell death characterized by swelling of the cytoplasm and mitochondria and rapid plasma membrane disruption. Necrotic cell death has long been opposed to apoptosis, but it now appears that both pathways involve mitochondrial permeability transition, raising the question of what mediates necrotic cell death. In this study, we investigated mechanisms that promote necrosis induced by various stimuli ( Clostridium difficile toxins, Staphylococcus aureus alpha toxin, ouabain, nigericin) in THP-1 cells, a human monocytic cell line, and in monocytes. All stimuli induced typical features of necrosis and triggered protease-mediated release of interleukin-1β (IL-1β) and CD14 in both cell types. K+depletion was actively implicated in necrosis because substituting K+for Na+in the extracellular medium prevented morphological features of necrosis and IL-1β release. N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, a broad-spectrum caspase inhibitor, prevented morphological features of necrosis, plasma membrane destruction, loss of mitochondrial membrane potential, IL-1β release, and CD14 shedding induced by all stimuli. Thus, in monocytic cells, necrosis is a cell death pathway mediated by passive K+efflux and activation of caspase-like proteases.

scholarly journals LRRC8 family proteins within lysosomes regulate cellular osmoregulation and enhance cell survival to multiple physiological stresses

2020 ◽  
Vol 117 (46) ◽  
pp. 29155-29165 ◽  
Author(s):  
Ping Li ◽  
Meiqin Hu ◽  
Ce Wang ◽  
Xinghua Feng ◽  
ZhuangZhuang Zhao ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Mammalian Cells ◽  
Essential Role ◽  
Multiple Stressors ◽  
Critical Role ◽  
Anion Channel ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
C Terminus

LRRC8 family proteins on the plasma membrane play a critical role in cellular osmoregulation by forming volume-regulated anion channels (VRACs) necessary to prevent necrotic cell death. We demonstrate that intracellular LRRC8 proteins acting within lysosomes also play an essential role in cellular osmoregulation. LRRC8 proteins on lysosome membranes generate large lysosomal volume-regulated anion channel (Lyso-VRAC) currents in response to low cytoplasmic ionic strength conditions. When a double-leucine L706L707motif at the C terminus of LRRC8A was mutated to alanines, normal plasma membrane VRAC currents were still observed, but Lyso-VRAC currents were absent. We used this targeting mutant, as well as pharmacological tools, to demonstrate that Lyso-VRAC currents are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis. Thus, Lyso-VRACs allow lysosomes of mammalian cells to act as the cell`s “bladder.” When Lyso-VRAC current was selectively eliminated, the extent of necrotic cell death to sustained stress was greatly increased, not only in response to hypoosmotic stress, but also to hypoxic and hypothermic stresses. Thus Lyso-VRACs play an essential role in enabling cells to mount successful homeostatic responses to multiple stressors.

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