scholarly journals P2X7 Receptor-Dependent and -Independent T Cell Death Is Induced by Nicotinamide Adenine Dinucleotide

2005 ◽  
Vol 174 (4) ◽  
pp. 1971-1979 ◽  
Author(s):  
Hiroki Kawamura ◽  
Fred Aswad ◽  
Masahiro Minagawa ◽  
Karen Malone ◽  
Harvey Kaslow ◽  
...  
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
P2x7 Receptor ◽  
Nicotinamide Adenine

scholarly journals Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayushi Chaurasiya ◽  
Swati Garg ◽  
Ashish Khanna ◽  
Chintam Narayana ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Malaria Parasite ◽  
Host Cells ◽  
Nicotinamide Adenine ◽  
Targeted Therapeutics ◽  
Nad Metabolism ◽  
Host Cell Death ◽  
Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

scholarly journals NAD+ cleavage activity by animal and plant TIR domains in cell death pathways

Science ◽  
2019 ◽  
Vol 365 (6455) ◽  
pp. 793-799 ◽  
Author(s):  
Shane Horsefield ◽  
Hayden Burdett ◽  
Xiaoxiao Zhang ◽  
Mohammad K. Manik ◽  
Yun Shi ◽  
...  
Keyword(s):  
Cell Death ◽  
Nicotinamide Adenine Dinucleotide ◽  
Interleukin 1 ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Effector Proteins ◽  
Nicotinamide Adenine ◽  
Cleavage Activity ◽  
Pathogen Effector ◽  
Cell Death Signaling ◽  
Tir Domains

SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD+) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association–dependent NAD+ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD+ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.

Mice Deficient for the Ecto-Nicotinamide Adenine Dinucleotide Glycohydrolase CD38 Exhibit Altered Humoral Immune Responses

Blood ◽  
1998 ◽  
Vol 92 (4) ◽  
pp. 1324-1333 ◽  
Author(s):  
Debra A. Cockayne ◽  
Tony Muchamuel ◽  
J. Christopher Grimaldi ◽  
Hélène Muller-Steffner ◽  
Troy D. Randall ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Antibody Responses ◽  
Nicotinamide Adenine ◽  
Humoral Immune ◽  
Nad Glycohydrolase ◽  
Humoral Immune Responses

Abstract CD38 is a membrane-associated ecto-nicotinamide adenine dinucleotide (NAD+) glycohydrolase that is expressed on multiple hematopoietic cells. The extracellular domain of CD38 can mediate the catalysis of NAD+ to cyclic adenosine diphosphoribose (cADPR), a Ca2+-mobilizing second messenger, adenosine diphosphoribose (ADPR), and nicotinamide. In addition to its enzymatic properties, murine CD38 has been shown to act as a B-cell coreceptor capable of modulating signals through the B-cell antigen receptor. To investigate the in vivo physiological function(s) of this novel class of ectoenzyme we generated mice carrying a null mutation in the CD38 gene. CD38−/− mice showed a complete loss of tissue-associated NAD+ glycohydrolase activity, showing that the classical NAD+ glycohydrolases and CD38 are likely identical. Although murine CD38 is expressed on hematopoietic stem cells as well as on committed progenitors, we show that CD38 is not required for hematopoiesis or lymphopoiesis. However, CD38−/− mice did exhibit marked deficiencies in antibody responses to T-cell–dependent protein antigens and augmented antibody responses to at least one T-cell–independent type 2 polysaccharide antigen. These data suggest that CD38 may play an important role in vivo in regulating humoral immune responses. © 1998 by The American Society of Hematology.

scholarly journals Extracellular Nicotinamide Adenine Dinucleotide Induces T Cell Apoptosis In Vivo and In Vitro

2001 ◽  
Vol 167 (9) ◽  
pp. 4942-4947 ◽  
Author(s):  
Zhang-Xu Liu ◽  
Olga Azhipa ◽  
Shigefumi Okamoto ◽  
Sugantha Govindarajan ◽  
Gunther Dennert
Keyword(s):  
T Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Cell Apoptosis ◽  
Nicotinamide Adenine ◽  
T Cell Apoptosis

scholarly journals The P2X7 Receptor in Tumor Immunity

2021 ◽  
Vol 9 ◽  
Author(s):  
Fabio Grassi ◽  
Benedetta De Ponte Conti
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
T Cell ◽  
P2x7 Receptor ◽  
Tissue Repair ◽  
Innate Immune ◽  
Tumor Control ◽  
Extracellular Adenosine ◽  
Molecular Pattern ◽  
Cell Immunity

Extracellular adenosine triphosphate (eATP) is a potent mediator of the immune response via stimulation of purinergic P2 receptors. ATP concentration in the extracellular space increases dramatically during tissue damage and eATP acts as a danger-associated molecular pattern (DAMP) to alert innate immune system cells for tissue repair. Similarly, eATP is present at hundreds of micromolar concentration in the tumor microenvironment (TME). However, its impact on antitumor immune response is still not well established, probably because of the complexity of the responses it induces in different cells constituting the TME. On one hand, ATP released by tumor cells concomitantly to cell death can contribute to immunogenic cell death (ICD) that is proinflammatory for the innate immune compartment and beneficial for tumor control, while on the other hand, eATP can foster immune-suppressive mechanisms within the TME, thus contributing to tumor progression and metastasis. It is well established that T-cell immunity is pivotal in limiting tumor growth and possibly eradicating neoplastic cells. T cells are limited though in their antitumor activity through different mechanisms, such as exhaustion, anergy, and senescence; the pathways resulting in these cellular outcomes are not clear. Here, we review the function of P2X7 receptor in conditioning T cell-dependent immunity against cancer.

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