Aminopeptidase MNP-1 triggers intestine protease production by activating daf-16 nuclear location to degrade pore-forming toxins in Caenorhabditis elegans.

Pore-forming toxins (PFTs) are effective tools for pathogens infection. By disrupting epithelial barriers and killing immune cells, PFTs promotes the colonization and reproduction of pathogenic microorganisms in their host. In turn, the host triggers defense responses, such as endocytosis, exocytosis, or autophagy. Bacillus thuringiensis (Bt) bacteria produce PFT, known as crystal proteins (Cry) which damage the intestinal cells of insects or nematodes, eventually killing them. In insects, aminopeptidase N (APN) has been shown to act as an important receptor for Cry toxins. Here, using the nematode Caenorhabditis elegans as model, an extensive screening of APN gene family was performed to analyze the potential role of these proteins in the mode of action of Cry5Ba against the nematode. We found that one APN, MNP-1, participate in the toxin defense response, since the mnp-1(ok2434) mutant showed a Cry5Ba hypersensitive phenotype. Gene expression analysis in mnp-1(ok2434) mutant revealed the involvement of two protease genes, F19C6.4 and R03G8.6, that participate in Cry5Ba degradation. Finally, analysis of the transduction pathway involved in F19C6.4 and R03G8.6 expression revealed that upon Cry5Ba exposure, the worms up regulated both protease genes through the activation of the FOXO transcription factor DAF-16, which was translocated into the nucleus. The nuclear location of DAF-16 was found to be dependent on mnp-1 under Cry5Ba treatment. Our work provides evidence of new host responses against PFTs produced by an enteric pathogenic bacterium, resulting in activation of host intestinal proteases that degrade the PFT in the intestine.

Autophagy-driven neutrophil extracellular traps: The dawn of sepsis.

Sepsis is a systemic inflammatory syndrome caused by infection disorders. The core mechanism of sepsis is immune dysfunction. Neutrophils are the most abundant circulating white blood cells, which play a crucial role in mediating the innate immune response. Previous studies have shown that an effective way to treat sepsis is through the regulation of neutrophil functions. Autophagy, a highly conserved degradation process, is responsible for removing denatured proteins or damaged organelles within cells and protecting cells from external stimuli. It is a key homeostasis process that promotes neutrophil function and differentiation. Autophagy has been shown to be closely associated with inflammation and immunity. Neutrophils, the first line of innate immunity, migrate to inflammatory sites upon their activation. Neutrophil-mediated autophagy may participate in the clinical course of sepsis. In this review, we summarized and analyzed the latest research findings on the changes in neutrophil external traps during sepsis, the regulatory role of autophagy in neutrophil, and the potential application of autophagy-driven NETs in sepsis, so as to guide clinical treatment of sepsis.