scholarly journals Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Laura Ramos Garcia ◽  
Tencho Tenev ◽  
Richard Newman ◽  
Rachel O. Haich ◽  
Gianmaria Liccardi ◽  
...  
Keyword(s):  
Cell Death ◽  
Tissue Injury ◽  
Higher Order ◽  
Skin Damage ◽  
Membrane Translocation ◽  
Cytotoxic Potential ◽  
Disease Pathogenesis ◽  
Signalling System ◽  
Membrane Rupture ◽  
Pathogen Clearance

AbstractNecroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.

scholarly journals Glycine targets NINJ1-mediated plasma membrane rupture to provide cytoprotection

2021 ◽  
Author(s):  
Jazlyn P Borges ◽  
Allen Volchuk ◽  
Bridget Kilburn ◽  
Neil M Goldenberg ◽  
Benjamin Ethan Steinberg
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Tissue Injury ◽  
Apoptotic Cell ◽  
Molecular Target ◽  
Tissue Preservation ◽  
Downstream Process ◽  
Membrane Rupture ◽  
Cell Death Pathways ◽  
Terminal Effector

First recognized more than 30 years ago, glycine is known to protect cells against plasma membrane rupture from diverse types of tissue injury. This robust and widely observed effect has been speculated to target a late downstream process common to multiple modes of tissue injury. The molecular target and mechanism of glycine cytoprotection, however, remain entirely elusive. We hypothesized that glycine targets ninjurin-1 (NINJ1), a newly identified executioner of plasma membrane rupture in pyroptosis, necrosis, and apoptotic cell death. This common terminal effector is thought to cluster within the plasma membrane to cause cell rupture. Here, we first demonstrate that NINJ1 knockout functionally and morphologically phenocopies glycine cytoprotection in macrophages stimulated to undergo lytic cell death. Glycine treatment in NINJ1 knockout cells provides no additional protective effect. Next, we show that glycine treatment prevents NINJ1 clustering within the plasma membrane thereby preserving its integrity. By identifying NINJ1 as a glycine target, our data help resolve the long-standing mechanism of glycine cytoprotection. This new understanding will inform the development of cell and tissue preservation strategies for pathologic conditions associated with lytic cell death pathways.

scholarly journals Enzyme-Treated Zizania latifolia Ethanol Extract Protects from UVA Irradiation-Induced Wrinkle Formation via Inhibition of Lysosome Exocytosis and Reactive Oxygen Species Generation

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 912
Author(s):  
Mirae An ◽  
Hyungkeun Kim ◽  
Joo-Myung Moon ◽  
Hyun-Soo Ko ◽  
Paul Clayton ◽  
...  
Keyword(s):  
Cathepsin B ◽  
Hydrolytic Enzyme ◽  
Reactive Oxygen Species Generation ◽  
Dermal Fibroblasts ◽  
Ros Generation ◽  
Skin Damage ◽  
Zizania Latifolia ◽  
Expression Levels ◽  
Membrane Rupture ◽  
Uva Irradiation

Ultraviolet A (UVA) is a risk factor for photoaging and wrinkle formation. Zizania latifolia is an herbaceous perennial plant. It contains many bioactive compounds such as tricin that show antioxidative and anti-inflammatory effects. The aim of this study was to investigate the antiwrinkle effect of a mixture of hydrolytic enzyme (cellulase, hemicellulase and pectinase)-treated Z. latifolia extract (ZLE) and tricin on UVA-irradiated human dermal fibroblasts (HDFs) and SKH-1 hairless mice. Treatment of UVA-irradiated HDF cells with ZLE and tricin significantly decreased UVA induced-plasma membrane rupture, generation of ROS, expression levels of total and secreted lysosomal associated membrane protein (LAMP-1), cathepsin B and metalloproteinases (MMPs) and inhibited NF-κB activation. In the animal study, UVA-damaged epidermal and dermal tissues were repaired by the ZLE and tricin treatments. Administration of ZLE or tricin to UVA-irradiated animals recovered skin surface moisture and collagen fiber in dermal tissue. Treatment of ZLE or tricin decreased wrinkle formation, secretion of MMPs and expression levels of vascular endothelial growth factor (VEGF) and cathepsin B, and increased the expression level of collagen-1 in UVA-irradiated animals. Overall, the ZLE and tricin treatments decreased the skin damage induced by UVA irradiation via inhibition of lysosomal exocytosis and ROS generation. Therefore, ZLE and tricin are promising as antiwrinkle and antiphotoaging agents.

scholarly journals Mitophagy: mechanisms, pathophysiological roles, and analysis

2012 ◽  
Vol 393 (7) ◽  
pp. 547-564 ◽  
Author(s):  
Wen-Xing Ding ◽  
Xiao-Ming Yin
Keyword(s):  
Cell Death ◽  
Blood Cells ◽  
Energy Homeostasis ◽  
Recent Progress ◽  
Tissue Injury ◽  
Current Knowledge ◽  
Terminal Differentiation ◽  
Cellular Functions ◽  
Drug Induced ◽  
Cellular Energy

Abstract Mitochondria are essential organelles that regulate cellular energy homeostasis and cell death. The removal of damaged mitochondria through autophagy, a process called mitophagy, is thus critical for maintaining proper cellular functions. Indeed, mitophagy has been recently proposed to play critical roles in terminal differentiation of red blood cells, paternal mitochondrial degradation, neurodegenerative diseases, and ischemia or drug-induced tissue injury. Removal of damaged mitochondria through autophagy requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition. Recent progress in mitophagy studies reveals that mitochondrial priming is mediated either by the Pink1-Parkin signaling pathway or the mitophagic receptors Nix and Bnip3. In this review, we summarize our current knowledge on the mechanisms of mitophagy. We also discuss the pathophysiological roles of mitophagy and current assays used to monitor mitophagy.

scholarly journals Repurposing Cationic Amphiphilic Drugs and Derivatives to Engage Lysosomal Cell Death in Cancer Treatment

2020 ◽  
Vol 10 ◽  
Author(s):  
Michelle Hu ◽  
Kermit L. Carraway
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Cellular Transformation ◽  
Therapeutic Window ◽  
Cell Populations ◽  
Necrotic Cell Death ◽  
Necrotic Cell ◽  
Membrane Rupture ◽  
Cationic Amphiphilic Drugs ◽  
Amphiphilic Drugs

A major confounding issue in the successful treatment of cancer is the existence of tumor cell populations that resist therapeutic agents and regimens. While tremendous effort has gone into understanding the biochemical mechanisms underlying resistance to each traditional and targeted therapeutic, a broader approach to the problem may emerge from the recognition that existing anti-cancer agents elicit their cytotoxic effects almost exclusively through apoptosis. Considering the myriad mechanisms cancer cells employ to subvert apoptotic death, an attractive alternative approach would leverage programmed necrotic mechanisms to side-step therapeutic resistance to apoptosis-inducing agents. Lysosomal cell death (LCD) is a programmed necrotic cell death mechanism that is engaged upon the compromise of the limiting membrane of the lysosome, a process called lysosomal membrane permeabilization (LMP). The release of lysosomal components into the cytosol upon LMP triggers biochemical cascades that lead to plasma membrane rupture and necrotic cell death. Interestingly, the process of cellular transformation appears to render the limiting lysosomal membranes of tumor cells more fragile than non-transformed cells, offering a potential therapeutic window for drug development. Here we outline the concepts of LMP and LCD, and discuss strategies for the development of agents to engage these processes. Importantly, the potential exists for existing cationic amphiphilic drugs such as antidepressants, antibiotics, antiarrhythmics, and diuretics to be repurposed to engage LCD within therapy-resistant tumor cell populations.

Improved clinical outcomes in pressure ulcer prevention using the SEM scanner

2019 ◽  
Vol 28 (5) ◽  
pp. 278-282 ◽  
Author(s):  
Glenn Smith
Keyword(s):  
Risk Assessment ◽  
Patient Outcomes ◽  
Pressure Ulcer ◽  
Tissue Injury ◽  
Skin Damage ◽  
Pressure Ulcer Prevention ◽  
Surgical Ward ◽  
Objective Evidence ◽  
Prevention Interventions ◽  
Assessment Strategies

Objective: An in-practice evaluation of an sub-epidermal moisture (SEM) scanner, to detect non-visible pressure damage, allowing appropriate, targeted pressure ulcer (PU) prevention interventions. Method: The evaluation included patients on a single medical-surgical ward over a period of two months. Results: The evaluation included 35 patients. The outcomes of the evaluation suggest that the SEM scanner provided objective evidence that both the interventions being employed and the increase in repositioning and assessment prevented further incipient skin damage. Conclusion: We conclude that the early detection of non-visible tissue injury using the SEM scanner as an adjunct to the usual PU risk assessment strategies can reduce PU incidence, leading to improved patient outcomes and released productivity.

Effect of Ischemia and Reperfusion on Skeletal Muscle Damage

2010 ◽  
Author(s):  
Sandra Loerakker ◽  
Emmy Manders ◽  
Gustav J. Strijkers ◽  
Frank P. T. Baaijens ◽  
Dan L. Bader ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Damage ◽  
Soft Tissues ◽  
Ischemia Reperfusion Injury ◽  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Ischemia And Reperfusion ◽  
Skin Damage ◽  
Deep Tissue ◽  
Skeletal Muscle Damage

Sustained mechanical loading of soft tissues covering bony prominences, as experienced by bedridden and wheelchair-bound individuals, may cause skeletal muscle damage. This can result in a condition termed pressure-related deep tissue injury (DTI), a severe kind of pressure ulcer that initiates in deep tissue layers, and progresses towards the skin. Damage pathways leading to DTI can involve ischemia, ischemia/reperfusion injury, impaired lymphatic drainage, and sustained tissue deformation. Recently, we have provided evidence that in a controlled animal model, deformation is the main trigger for damage within a 2h loading period [1,2]. However, ischemia and reperfusion may play a more important role in the damage process during prolonged loading periods.

scholarly journals The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1313
Author(s):  
Man Wang ◽  
Shuai Jiang ◽  
Yinfeng Zhang ◽  
Peifeng Li ◽  
Kun Wang
Keyword(s):  
Cell Death ◽  
Biological Significance ◽  
Chemotherapeutic Agents ◽  
The Body ◽  
Cell Swelling ◽  
Pathogen Invasion ◽  
Membrane Rupture ◽  
Cancer Management ◽  
Cell Death Pathways ◽  
Cancer Pathogenesis

Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility.

scholarly journals Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Bartosz Wiernicki ◽  
Hanne Dubois ◽  
Yulia Y. Tyurina ◽  
Behrouz Hassannia ◽  
Hülya Bayir ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
The Other ◽  
Strong Increase ◽  
Oxygen Species ◽  
Membrane Rupture ◽  
Regulated Cell Death ◽  
Phospholipid Peroxidation ◽  
Differential Involvement

Abstract Lipid peroxidation (LPO) drives ferroptosis execution. However, LPO has been shown to contribute also to other modes of regulated cell death (RCD). To clarify the role of LPO in different modes of RCD, we studied in a comprehensive approach the differential involvement of reactive oxygen species (ROS), phospholipid peroxidation products, and lipid ROS flux in the major prototype modes of RCD viz. apoptosis, necroptosis, ferroptosis, and pyroptosis. LC-MS oxidative lipidomics revealed robust peroxidation of three classes of phospholipids during ferroptosis with quantitative predominance of phosphatidylethanolamine species. Incomparably lower amounts of phospholipid peroxidation products were found in any of the other modes of RCD. Nonetheless, a strong increase in lipid ROS levels was detected in non-canonical pyroptosis, but only during cell membrane rupture. In contrast to ferroptosis, lipid ROS apparently was not involved in non-canonical pyroptosis execution nor in the release of IL-1β and IL-18, while clear dependency on CASP11 and GSDMD was observed. Our data demonstrate that ferroptosis is the only mode of RCD that depends on excessive phospholipid peroxidation for its cytotoxicity. In addition, our results also highlight the importance of performing kinetics and using different methods to monitor the occurrence of LPO. This should open the discussion on the implication of particular LPO events in relation to different modes of RCD.

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