Plant mixed lineage kinase domain-like proteins limit biotrophic pathogen growth

AbstractMixed lineage kinase domain-like (MLKL) protein mediates necroptotic cell death in vertebrates. We report here the discovery of a conserved protein family across seed plants that is structurally homologous to vertebrate MLKL. TheArabidopsis thalianagenome encodes three MLKLs with overlapping functions in limiting growth of obligate biotrophic fungal and oomycete pathogens. Although displaying a cell death activity mediated by N-terminal helical bundles, termed HeLo domain,AtMLKL-dependent immunity can be separated from host cell death. Cryo-electron microscopy structures ofAtMLKLs reveal a tetrameric configuration, in which the pseudokinase domain and brace region bury the HeLo-domains, indicative of an auto-repressed complex. We also show the association of twoAtMLKLs with microtubules. These findings, coupled with resistance-enhancing activity and altered microtubule association of a phosphomimetic mutation in the pseudokinase domain ofAtMLKL1, point to a cell death-independent immunity mechanism.One Sentence SummaryPlants have a protein family that is structurally homologous to vertebrate mixed lineage kinase domain-like protein, which induces necroptotic cell death, but these plant proteins can confer immunity without host cell death.

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Faculty Opinions recommendation of Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.13988977.15445089 ◽

2012 ◽

Author(s):

Thierry Soldati ◽

Sonia Arafah

Keyword(s):

Cell Death ◽

Mycobacterium Tuberculosis ◽

Host Cell ◽

Host Cell Death

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

Cell Death Discovery ◽

10.1038/s41420-020-00366-z ◽

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.

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Macrophage Activation Redirects Yersinia-Infected Host Cell Death from Apoptosis to Caspase-1-Dependent Pyroptosis

PLoS Pathogens ◽

10.1371/journal.ppat.0030161 ◽

2007 ◽

Vol 3 (11) ◽

pp. e161 ◽

Cited By ~ 133

Author(s):

Tessa Bergsbaken ◽

Brad T Cookson

Keyword(s):

Cell Death ◽

Host Cell ◽

Macrophage Activation ◽

Infected Host ◽

Infected Host Cell ◽

Caspase 1 ◽

Host Cell Death

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Kinetic Effect of Silkworm Hemolymph on the Delayed Host Cell Death in an Insect Cell-Baculovirus System

Biotechnology Progress ◽

10.1021/bp990093s ◽

1999 ◽

Vol 15 (6) ◽

pp. 1028-1032 ◽

Cited By ~ 39

Author(s):

W.J. Rhee ◽

E.J. Kim ◽

T.H. Park

Keyword(s):

Cell Death ◽

Host Cell ◽

Insect Cell ◽

Kinetic Effect ◽

Silkworm Hemolymph ◽

Host Cell Death ◽

Baculovirus System

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TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

Infection and Immunity ◽

10.1128/iai.00044-14 ◽

2014 ◽

Vol 82 (5) ◽

pp. 2068-2078 ◽

Cited By ~ 16

Author(s):

Christopher R. Doyle ◽

Ji-An Pan ◽

Patricio Mena ◽

Wei-Xing Zong ◽

David G. Thanassi

Keyword(s):

Cell Death ◽

Immune Responses ◽

Host Cell ◽

Francisella Tularensis ◽

Vaccine Strain ◽

Live Vaccine ◽

Live Vaccine Strain ◽

Type I ◽

Content Type ◽

Host Cell Death

ABSTRACTFrancisella tularensisis a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of theF. tularensislive vaccine strain (LVS) and demonstrated that a ΔtolCmutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required forF. tularensisto preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ΔtolCmutant. These findings support a model wherein the immunomodulatory capacity ofF. tularensisrelies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ΔtolCLVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ΔtolCmutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection byF. tularensisand highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

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