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ACS Infect Dis. 2018 Dec 14;4(12):1746-1754. doi: 10.1021/acsinfecdis.8b00231. Epub 2018 Nov 5.

Role of a Small Molecule in the Modulation of Cell Death Signal Transduction Pathways.

Author information

1
School of Applied Life Sciences , Keck Graduate Institute , 535 Watson Drive , Claremont , California 91711 , United States.
2
Department of Microbiology, Immunology and Molecular Genetics , University of California, Los Angeles , 609 Charles E. Young Drive East , Los Angeles , California 90095 , United States.

Abstract

Inflammasomes activate caspase-1 in response to molecular signals from pathogens and other dangerous stimuli as a part of the innate immune response. A previous study discovered a small-molecule, 4-fluoro- N'-[1-(2-pyridinyl)ethylidene]benzohydrazide, which we named DN1, that reduces the cytotoxicity of anthrax lethal toxin (LT). We determined that DN1 protected cells irrespectively of LT concentration and reduced the pathogenicity of an additional bacterial exotoxin and several viruses. Using the LT cytotoxicity pathway, we show that DN1 does not prevent LT internalization and catalytic activity or caspase-1 activation. Moreover, DN1 does not affect the proteolytic activity of host cathepsin B, which facilitates the cytoplasmic entry of toxins. PubChem Bioactivities lists two G protein-coupled receptors (GPCR), type-1 angiotensin II receptor and apelin receptor, as targets of DN1. The inhibition of phosphatidylinositol 3-kinase, phospholipase C, and protein kinase B, which are downstream of GPCR signaling, synergized with DN1 in protecting cells from LT. We hypothesize that DN1-mediated antagonism of GPCRs modulates signal transduction pathways to induce a cellular state that reduces LT-induced pyroptosis downstream of caspase-1 activation. DN1 also reduced the susceptibility of Drosophila melanogaster to toxin-associated bacterial infections. Future experiments will aim to further characterize how DN1 modulates signal transduction pathways to inhibit pyroptotic cell death in LT-sensitive macrophages. DN1 represents a novel chemical probe to investigate host cellular mechanisms that mediate cell death in response to pathogenic agents.

KEYWORDS:

G protein-coupled receptor; anthrax toxin; broad-spectrum; drug discovery; host-oriented; pyroptosis

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