scholarly journals Necroptotic Cell Death Signaling and Execution Pathway: Lessons from Knockout Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
José Belizário ◽  
Luiz Vieira-Cordeiro ◽  
Sylvia Enns
Keyword(s):  
Cell Death ◽  
Knockout Mice ◽  
Critical Role ◽  
Stress Conditions ◽  
Dna Integrity ◽  
Caspase 8 ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Injury Death ◽  
Regulated Necrosis

Under stress conditions, cells in living tissue die by apoptosis or necrosis depending on the activation of the key molecules within a dying cell that either transduce cell survival or death signals that actively destroy the sentenced cell. Multiple extracellular (pH, heat, oxidants, and detergents) or intracellular (DNA damage and Ca2+overload) stress conditions trigger various types of the nuclear, endoplasmic reticulum (ER), cytoplasmatic, and mitochondrion-centered signaling events that allow cells to preserve the DNA integrity, protein folding, energetic, ionic and redox homeostasis, thus escaping from injury. Along the transition from reversible to irreversible injury, death signaling is highly heterogeneous and damaged cells may engage autophagy, apoptotic, or necrotic cell death programs. Studies on multiple double- and triple- knockout mice identifiedcaspase-8,flip, andfaddgenes as key regulators of embryonic lethality and inflammation. Caspase-8 has a critical role in pro- and antinecrotic signaling pathways leading to the activation of receptor interacting protein kinase 1 (RIPK1), RIPK3, and the mixed kinase domain-like (MLKL) for a convergent execution pathway of necroptosis or regulated necrosis. Here we outline the recent discoveries into how the necrotic cell death execution pathway is engaged in many physiological and pathological outcome based on genetic analysis of knockout mice.

scholarly journals A major role for ferroptosis in Mycobacterium tuberculosis–induced cell death and tissue necrosis

2019 ◽  
Vol 216 (3) ◽  
pp. 556-570 ◽  
Author(s):  
Eduardo P. Amaral ◽  
Diego L. Costa ◽  
Sivaranjani Namasivayam ◽  
Nicolas Riteau ◽  
Olena Kamenyeva ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Lipid Peroxides ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Free Iron ◽  
Regulated Necrosis

Necrotic cell death during Mycobacterium tuberculosis (Mtb) infection is considered host detrimental since it facilitates mycobacterial spread. Ferroptosis is a type of regulated necrosis induced by accumulation of free iron and toxic lipid peroxides. We observed that Mtb-induced macrophage necrosis is associated with reduced levels of glutathione and glutathione peroxidase-4 (Gpx4), along with increased free iron, mitochondrial superoxide, and lipid peroxidation, all of which are important hallmarks of ferroptosis. Moreover, necrotic cell death in Mtb-infected macrophage cultures was suppressed by ferrostatin-1 (Fer-1), a well-characterized ferroptosis inhibitor, as well as by iron chelation. Additional experiments in vivo revealed that pulmonary necrosis in acutely infected mice is associated with reduced Gpx4 expression as well as increased lipid peroxidation and is likewise suppressed by Fer-1 treatment. Importantly, Fer-1–treated infected animals also exhibited marked reductions in bacterial load. Together, these findings implicate ferroptosis as a major mechanism of necrosis in Mtb infection and as a target for host-directed therapy of tuberculosis.

scholarly journals Cell Death Induction and Protection by Activation of Ubiquitously Expressed Anion/Cation Channels. Part 1: Roles of VSOR/VRAC in Cell Volume Regulation, Release of Double-Edged Signals and Apoptotic/Necrotic Cell Death

2021 ◽  
Vol 8 ◽  
Author(s):  
Yasunobu Okada ◽  
Ravshan Z. Sabirov ◽  
Kaori Sato-Numata ◽  
Tomohiro Numata
Keyword(s):  
Cell Death ◽  
Cell Volume ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Cell Swelling ◽  
Cation Channels ◽  
Necrotic Cell Death ◽  
Anion Channels ◽  
Necrotic Cell ◽  
Regulated Necrosis

Cell volume regulation (CVR) is essential for survival and functions of animal cells. Actually, normotonic cell shrinkage and swelling are coupled to apoptotic and necrotic cell death and thus called the apoptotic volume decrease (AVD) and the necrotic volume increase (NVI), respectively. A number of ubiquitously expressed anion and cation channels are involved not only in CVD but also in cell death induction. This series of review articles address the question how cell death is induced or protected with using ubiquitously expressed ion channels such as swelling-activated anion channels, acid-activated anion channels and several types of TRP cation channels including TRPM2 and TRPM7. The Part 1 focuses on the roles of the volume-sensitive outwardly rectifying anion channels (VSOR), also called the volume-regulated anion channel (VRAC), which is activated by cell swelling or reactive oxygen species (ROS) in a manner dependent on intracellular ATP. First we describe phenotypical properties, the molecular identity, and physical pore dimensions of VSOR/VRAC. Second, we highlight the roles of VSOR/VRAC in the release of organic signaling molecules, such as glutamate, glutathione, ATP and cGAMP, that play roles as double-edged swords in cell survival. Third, we discuss how VSOR/VRAC is involved in CVR and cell volume dysregulation as well as in the induction of or protection from apoptosis, necrosis and regulated necrosis under pathophysiological conditions.

scholarly journals Origin and Consequences of Necroinflammation

2018 ◽  
Vol 98 (2) ◽  
pp. 727-780 ◽  
Author(s):  
Maysa Sarhan ◽  
Walter G. Land ◽  
Wulf Tonnus ◽  
Christian P. Hugo ◽  
Andreas Linkermann
Keyword(s):  
Cell Death ◽  
Immune System ◽  
Current Knowledge ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Relative Contribution ◽  
Regulated Necrosis ◽  
Genetically Determined ◽  
Molecular Patterns

When cells undergo necrotic cell death in either physiological or pathophysiological settings in vivo, they release highly immunogenic intracellular molecules and organelles into the interstitium and thereby represent the strongest known trigger of the immune system. With our increasing understanding of necrosis as a regulated and genetically determined process (RN, regulated necrosis), necrosis and necroinflammation can be pharmacologically prevented. This review discusses our current knowledge about signaling pathways of necrotic cell death as the origin of necroinflammation. Multiple pathways of RN such as necroptosis, ferroptosis, and pyroptosis have been evolutionary conserved most likely because of their differences in immunogenicity. As the consequence of necrosis, however, all necrotic cells release damage associated molecular patterns (DAMPs) that have been extensively investigated over the last two decades. Analysis of necroinflammation allows characterizing specific signatures for each particular pathway of cell death. While all RN-pathways share the release of DAMPs in general, most of them actively regulate the immune system by the additional expression and/or maturation of either pro- or anti-inflammatory cytokines/chemokines. In addition, DAMPs have been demonstrated to modulate the process of regeneration. For the purpose of better understanding of necroinflammation, we introduce a novel classification of DAMPs in this review to help detect the relative contribution of each RN-pathway to certain physiological and pathophysiological conditions.

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.

Abstract 373: Identification of Novel Anti-necrotic Factor TGN91

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jason Karch ◽  
Matthew J Brody ◽  
Onur Kanisicak ◽  
Michelle A Sargent ◽  
Jeffery D Molkentin
Keyword(s):  
Cell Death ◽  
Transmembrane Protein ◽  
Calcium Ionophore ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Ischemic Insult ◽  
Regulated Necrosis ◽  
Mechanistic Basis ◽  
Definition Of ◽  
Golgi Network

Loss of cardiomyocytes by necrotic cell death is the direct mechanistic basis for mortality due to myocardial infarction injury, as well as ensuing heart failure associated with an array of cardiomyopathies. Further definition of the regulated necrotic pathway and identification of novel effectors will be essential in designing new therapies. To identify novel regulators of necrotic cell death we performed an unbiased lentiviral-based overexpression screen comprising of over 13,000 human cDNAs. In order to mimic an ischemic insult, the calcium ionophore ionomycin was used to induce necrotic cell death in conjunction with each individually encoded cDNA in the lentiviruses. After 24 hours of calcium overload cell viability was assessed to determine if a cDNA had a protective or maladaptive effect on necrotic cell death. One completely novel cDNA that we named Trans-Golgi Network protein 91 (TGN91) was found to be significantly protective against regulated necrosis. TGN91 is a multipass transmembrane protein that is conserved from humans to drosophila, although its function is unknown. TGN91 is most abundant in the heart compared to other tissues in the mouse and the protein resides within the Golgi. The expression of TGN91 increases in human ischemic failing hearts compared to non-ischemic failing and normal hearts. Lastly, we generated transgenic mice overexpressing TGN91 specifically in cardiomyocytes and our preliminary results suggest that these mice are protected against ischemic injury. The identification of TGN91 not only provides a novel putative regulator of the necrotic pathway, but also advocates for the Golgi as a regulatory site in necrotic cell death.

scholarly journals BopC Is a Novel Type III Effector Secreted byBordetella bronchisepticaand Has a Critical Role in Type III-dependent Necrotic Cell Death

2006 ◽  
Vol 281 (10) ◽  
pp. 6589-6600 ◽  
Author(s):  
Asaomi Kuwae ◽  
Takeshi Matsuzawa ◽  
Naoto Ishikawa ◽  
Hiroyuki Abe ◽  
Takashi Nonaka ◽  
...  
Keyword(s):  
Cell Death ◽  
Critical Role ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Type Iii Effector ◽  
Type Iii

scholarly journals Necrotic Cell Death in Response to Oxidant Stress Involves the Activation of the Apoptogenic Caspase-8/Bid Pathway

2003 ◽  
Vol 278 (31) ◽  
pp. 29184-29191 ◽  
Author(s):  
Xue Wang ◽  
Stefan W. Ryter ◽  
Chunsun Dai ◽  
Zi-Lue Tang ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
Cell Death ◽  
Oxidant Stress ◽  
Caspase 8 ◽  
Necrotic Cell Death ◽  
Necrotic Cell

Oleanolic acid rich solubilized triterpene extracts from mistletoe induce apoptotic and necrotic cell death of murine B16. F10 melanoma cells

Planta Medica ◽  
2009 ◽  
Vol 75 (09) ◽  
Author(s):  
CM Strüh ◽  
S Jäger ◽  
CM Schempp ◽  
T Jakob ◽  
A Scheffler ◽  
...  
Keyword(s):  
Cell Death ◽  
Oleanolic Acid ◽  
Melanoma Cells ◽  
Necrotic Cell Death ◽  
Necrotic Cell
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