Related Experiment Video

Updated: Jul 7, 2026

Bone Marrow-derived Macrophage Production
07:06

Bone Marrow-derived Macrophage Production

Published on: November 22, 2013

Killing of macrophages by anthrax lethal toxin: involvement of the N-end rule pathway

Katherine E Wickliffe1, Stephen H Leppla, Mahtab Moayeri

  • 1Bacterial Toxins and Therapeutics Section, Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Cellular Microbiology
|February 13, 2008
PubMed

Insights

Anthrax lethal toxin (LT) rapidly kills macrophages by degrading the c-IAP1 protein via the N-end rule pathway. Inhibiting this degradation protects against LT-induced cell death.

Area of Science:

  • Cell Biology
  • Immunology
  • Toxicology

Background:

  • Anthrax lethal toxin (LT) causes rapid death in macrophages from specific mouse strains.
  • The precise mechanism of LT-induced macrophage death remains unclear.
  • LT cleaves MEK proteins and activates caspase-1 in sensitive macrophages.

Purpose of the Study:

  • To elucidate the mechanism of anthrax lethal toxin-induced macrophage death.
  • To identify cellular proteins and pathways involved in LT-mediated cytotoxicity.
  • To explore potential therapeutic strategies against LT toxicity.

Main Methods:

  • Utilized proteasome inhibitors and N-end rule pathway inhibitors (amino acid derivatives).
  • Administered bestatin methyl ester, an aminopeptidase inhibitor, in vitro and in vivo.
  • Investigated the degradation of c-IAP1 (an inhibitor of apoptosis protein) in LT-treated macrophages.
  • Assessed the role of Smac/DIABLO and Omi/HtrA2 in LT-induced c-IAP1 degradation.

Main Results:

  • Proteasome inhibitors blocked LT-mediated caspase-1 activation and protected against cell death.
  • The N-end rule pathway is essential for LT-induced caspase-1 activation and macrophage death.
  • Bestatin methyl ester demonstrated protective effects against LT.
  • Inhibitors of the protein degradation pathway exhibited synergistic protection against LT.
  • Identified c-IAP1 as a novel N-end rule substrate degraded by LT.
  • LT-induced c-IAP1 degradation was independent of Smac/DIABLO and Omi/HtrA2 but dependent on caspases.

Conclusions:

  • Macrophage death induced by anthrax lethal toxin requires the degradation of cellular proteins via the N-end rule pathway.
  • c-IAP1 is a key N-end rule substrate degraded during LT intoxication.
  • Targeting protein degradation pathways, particularly the N-end rule, offers a potential therapeutic strategy against anthrax lethal toxin.

More Related Videos

LPS and ATP-induced Death of PMA-differentiated THP-1 Macrophages and its Validation06:12

LPS and ATP-induced Death of PMA-differentiated THP-1 Macrophages and its Validation

Published on: May 3, 2024

Isolation of Salmonella typhimurium-containing Phagosomes from Macrophages10:33

Isolation of Salmonella typhimurium-containing Phagosomes from Macrophages

Published on: October 25, 2017

Related Concept Videos

Inhalation Anthrax01:25

Inhalation Anthrax

Anthrax is a zoonotic disease caused by Bacillus anthracis, a Gram-positive, spore-forming bacterium. It primarily affects herbivorous animals but can be transmitted to humans through skin contact, ingestion, or inhalation of spores.Cutaneous anthrax, the most common form, typically results from direct contact with bacterial spores through skin abrasions and is generally less severe. Gastrointestinal anthrax results from eating undercooked or contaminated meat. It affects the mouth, throat, or...
Receptor-mediated Endocytosis01:20

Receptor-mediated Endocytosis

Receptor-mediated endocytosis is when bulk amounts of specific molecules are imported into a cell after binding to cell surface receptors. The molecules bound to these receptors are taken into the cell through inward folding of the cell surface membrane, which is eventually pinched off into a vesicle within the cell. Structural proteins, such as clathrin, coat the budding vesicle.
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
Receptor-mediated Endocytosis01:38

Receptor-mediated Endocytosis

Overview
Bacterial Toxins01:12

Bacterial Toxins

Bacterial toxins are sophisticated virulence factors that enable pathogenic bacteria to interact with, invade, and damage host tissues. These toxins fall broadly into two types: protein exotoxins, which are secreted into the environment and target specific host receptors, and lipopolysaccharide endotoxins, which are structural components of the bacterial outer membrane released primarily during bacterial lysis or membrane shedding. Exotoxins generally act more selectively, binding to cell...
The Extrinsic Apoptotic Pathway01:17

The Extrinsic Apoptotic Pathway

The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
Phagocytosis of Apoptotic Cells01:17

Phagocytosis of Apoptotic Cells

Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or  immature dendritic cells. Non-professional phagocytes such as  epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes. 
Normal cells contain receptors that prevent them from being recognized by phagocytes.