scholarly journals Apoptotic pathways are selectively activated by granzyme A and/or granzyme B in CTL-mediated target cell lysis

2004 ◽  
Vol 167 (3) ◽  
pp. 457-468 ◽  
Author(s):  
Julián Pardo ◽  
Alberto Bosque ◽  
Reina Brehm ◽  
Reinhard Wallich ◽  
Javier Naval ◽  
...  
Keyword(s):  
Cell Death ◽  
Target Cell ◽  
Ex Vivo ◽  
Reactive Oxygen ◽  
Phosphatidyl Serine ◽  
Oxygen Scavengers ◽  
Cell Death Pathways ◽  
Physiological Relevance ◽  
Apoptotic Pathways ◽  
Tumor Target Cell

Purified cytolytic T lymphocyte (CTL) proteases granzyme (gzm)A and gzmB with sublytic dose of perforin (perf) initiate distinct proapoptotic pathways. Their physiological relevance in CTL-mediated target cell apoptosis is elusive. Using ex vivo virus-immune CD8+ T cells from mice deficient in perf, gzmA and/or gzmB, and the Fas-resistant EL4.F15 tumor target cell, we show that (a) CTL from gzmA−/− or gzmB−/− mice similarly induced early proapoptotic features, such as phosphatidyl serine (PS) exposure on plasma membrane, ΔΨm loss, and reactive oxygen radical generation, though with distinct kinetics; (b) CTL from gzmA−/− but not from gzmB−/− mice activate caspase 3 and 9; (c) PS exposure induced by CTL from gzmA−/− or gzmB−/− mice is prevented, respectively, by caspase inhibitors or by reactive oxygen scavengers without interfering with target cell death; and (d) all gzm-induced apoptotic features analyzed depend critically on perf. Thus, perf is the principal regulator in CTL-mediated and gzm-facilitated intracellular processes. The ability of gzmA and gzmB to induce multiple independent cell death pathways may be the hosts response to circumvent evasion strategies of pathogens and tumors.

Targeting multiple cell death pathways extends the shelf life and preserves the function of human and mouse neutrophils for transfusion

2021 ◽  
Vol 13 (604) ◽  
pp. eabb1069
Author(s):  
Yuping Fan ◽  
Yan Teng ◽  
Fabien Loison ◽  
Aiming Pang ◽  
Anongnard Kasorn ◽  
...  
Keyword(s):  
Cell Death ◽  
Shelf Life ◽  
Ex Vivo ◽  
Combined Treatment ◽  
Bacterial Killing ◽  
Immunodeficient Mice ◽  
Cell Death Pathways ◽  
Multiple Cell ◽  
Human And Mouse

Clinical outcomes from granulocyte transfusion (GTX) are disadvantaged by the short shelf life and compromised function of donor neutrophils. Spontaneous neutrophil death is heterogeneous and mediated by multiple pathways. Leveraging mechanistic knowledge and pharmacological screening, we identified a combined treatment, caspases–lysosomal membrane permeabilization–oxidant–necroptosis inhibition plus granulocyte colony-stimulating factor (CLON-G), which altered neutrophil fate by simultaneously targeting multiple cell death pathways. CLON-G prolonged human and mouse neutrophil half-life in vitro from less than 1 day to greater than 5 days. CLON-G–treated aged neutrophils had equivalent morphology and function to fresh neutrophils, with no impairment to critical effector functions including phagocytosis, bacterial killing, chemotaxis, and reactive oxygen species production. Transfusion with stored CLON-G–treated 3-day-old neutrophils enhanced host defenses, alleviated infection-induced tissue damage, and prolonged survival as effectively as transfusion with fresh neutrophils in a clinically relevant murine GTX model of neutropenia-related bacterial pneumonia and systemic candidiasis. Last, CLON-G treatment prolonged the shelf life and preserved the function of apheresis-collected human GTX products both ex vivo and in vivo in immunodeficient mice. Thus, CLON-G treatment represents an effective and applicable clinical procedure for the storage and application of neutrophils in transfusion medicine, providing a therapeutic strategy for improving GTX efficacy.

scholarly journals OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

2021 ◽  
Author(s):  
Daisuke Oikawa ◽  
Min Gi ◽  
Hidetaka Kosako ◽  
Kouhei Shimizu ◽  
Hirotaka Takahashi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Stress Responses ◽  
Inflammatory Responses ◽  
Reactive Oxygen ◽  
Antioxidant Response ◽  
Oxygen Species ◽  
Ubiquitin Chain ◽  
Intrinsically Disordered ◽  
Cell Death Pathways

Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

scholarly journals The role of Ubiquitination in Apoptosis and Necroptosis

2021 ◽  
Author(s):  
Jamie Z. Roberts ◽  
Nyree Crawford ◽  
Daniel B. Longley
Keyword(s):  
Cell Death ◽  
Death Receptors ◽  
Tnf Receptor ◽  
Extrinsic Pathway ◽  
Post Translational Modifications ◽  
Cell Death Pathways ◽  
Apoptotic Pathways ◽  
Extrinsic Apoptotic Pathways ◽  
Necrosis Factor

AbstractCell death pathways have evolved to maintain tissue homoeostasis and eliminate potentially harmful cells from within an organism, such as cells with damaged DNA that could lead to cancer. Apoptosis, known to eliminate cells in a predominantly non-inflammatory manner, is controlled by two main branches, the intrinsic and extrinsic apoptotic pathways. While the intrinsic pathway is regulated by the Bcl-2 family members, the extrinsic pathway is controlled by the Death receptors, members of the tumour necrosis factor (TNF) receptor superfamily. Death receptors can also activate a pro-inflammatory type of cell death, necroptosis, when Caspase-8 is inhibited. Apoptotic pathways are known to be tightly regulated by post-translational modifications, especially by ubiquitination. This review discusses research on ubiquitination-mediated regulation of apoptotic signalling. Additionally, the emerging importance of ubiquitination in regulating necroptosis is discussed.

scholarly journals Role of Mitochondrial Calcium and the Permeability Transition Pore in Regulating Cell Death

2020 ◽  
Vol 126 (2) ◽  
pp. 280-293 ◽  
Author(s):  
Tyler M. Bauer ◽  
Elizabeth Murphy
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Mitochondrial Calcium ◽  
Oxygen Species ◽  
Inner Mitochondrial Membrane ◽  
Atp Production ◽  
Cell Death Pathways

Adult cardiomyocytes are postmitotic cells that undergo very limited cell division. Thus, cardiomyocyte death as occurs during myocardial infarction has very detrimental consequences for the heart. Mitochondria have emerged as an important regulator of cardiovascular health and disease. Mitochondria are well established as bioenergetic hubs for generating ATP but have also been shown to regulate cell death pathways. Indeed many of the same signals used to regulate metabolism and ATP production, such as calcium and reactive oxygen species, are also key regulators of mitochondrial cell death pathways. It is widely hypothesized that an increase in calcium and reactive oxygen species activate a large conductance channel in the inner mitochondrial membrane known as the PTP (permeability transition pore) and that opening of this pore leads to necroptosis, a regulated form of necrotic cell death. Strategies to reduce PTP opening either by inhibition of PTP or inhibiting the rise in mitochondrial calcium or reactive oxygen species that activate PTP have been proposed. A major limitation of inhibiting the PTP is the lack of knowledge about the identity of the protein(s) that form the PTP and how they are activated by calcium and reactive oxygen species. This review will critically evaluate the candidates for the pore-forming unit of the PTP and discuss recent data suggesting that assumption that the PTP is formed by a single molecular identity may need to be reconsidered.

scholarly journals The target cell nucleus is not required for cell-mediated granzyme- or Fas-based cytotoxicity.

1995 ◽  
Vol 181 (5) ◽  
pp. 1905-1909 ◽  
Author(s):  
H Nakajima ◽  
P Golstein ◽  
P A Henkart
Keyword(s):  
Cell Death ◽  
Target Cell ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Cell Nuclei ◽  
Effector Cells ◽  
Cell Death Pathways ◽  
Mast Cell Tumors ◽  
Nuclear Damage

The requirement for target cell nuclei in the two apoptotic death pathways used by cytotoxic lymphocytes was tested using model effector systems in which the granzyme and Fas pathways of target damage are isolated. Mast cell tumors expressing granzymes A and B in addition to cytolysin/perforin lysed tumor target cells about 10-fold more efficiently than comparable effector cells without granzymes. Enucleated cytoplast targets derived from these cells were also lysed with a similar 10-fold effect of granzymes. In contrast to cytoplasts, effector granzyme expression did not influence lysis of red cell targets. The Fas pathway was assessed using the selected cytotoxic T lymphocyte hybridoma subline d11S, which lysed target cells expressing Fas but not those lacking Fas. Similarly, cytoplasts derived from Fas+ but not Fas- cells were also readily lysed by these effector cells. Thus, neither the nucleus itself nor the characteristic apoptotic nuclear damage associated with the two major cell death pathways used by cytotoxic lymphocytes are required for cell death per se.

Presenilin-interacting proteins

2002 ◽  
Vol 4 (19) ◽  
pp. 1-18 ◽  
Author(s):  
Qi Chen ◽  
David Schubert
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Cell Types ◽  
Cellular Adhesion ◽  
Interacting Proteins ◽  
Missense Mutations ◽  
Cell Death Pathways ◽  
Physiological Relevance ◽  
Genes Encoding

Familial Alzheimer's disease (FAD) accounts for 5–10% of deaths from Alzheimer's disease (AD), and approximately 50% of these cases have been definitely linked to missense mutations in three genes, encoding the amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Of these, the vast majority of FAD-linked mutations are within PS1. There has been an extensive effort to identify proteins that functionally interact with PS1 and PS2 because of their clear roles in FAD. The goal of this review is to describe these proteins and to discuss in more detail the probable biological functions of a subset of the better-studied interacting proteins. In particular, the review examines APP, Notch, nicastrin, modifier of cellular adhesion (MOCA), β-catenin, and the group of proteins involved in cell death, calcium metabolism and cell adhesion. We argue that, although a few of the interacting proteins are unambiguously involved in well-studied cellular pathways, their exact roles within these pathways have not been clearly defined, and indeed might vary between cell types. We also question the physiological relevance of some of the work linking PS to cell death pathways. Finally, we point out the value of using flies and worms to sort out the often contradictory work in the PS field, and we mention how knowledge of PS-interacting pathways will contribute to the development of new therapeutic strategies in AD.

Holographic monitoring of cell death pathways induced by reactive oxygen species

2018 ◽  
Author(s):  
A.V. Belashov ◽  
A.A. Zhikhoreva ◽  
D.A. Rogova ◽  
T.N. Belyaeva ◽  
E.S. Kornilova ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cell Death Pathways

scholarly journals Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo

Retrovirology ◽  
2014 ◽  
Vol 11 (1) ◽  
pp. 14 ◽  
Author(s):  
Amanda K Steele ◽  
Eric J Lee ◽  
Jennifer A Manuzak ◽  
Stephanie M Dillon ◽  
John Beckham ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Ex Vivo ◽  
Cd4 T Cell ◽  
Cell Death Pathways ◽  
Microbial Exposure ◽  
Hiv 1
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