Spatiotemporal proteomics uncovers cathepsin-dependent host cell death during bacterial infection

BioRxiv : the Preprint Server for Biology
Joel SelkrigAthanasios Typas

Abstract

Immune cells need to swiftly and effectively respond to invading pathogens. This response relies heavily on rapid protein synthesis and accurate cellular targeting to ensure pathogen destruction. In return, pathogens intercept this response to ensure their survival and proliferation. To gain insight into this dynamic interface, we combined click-chemistry with pulsed stable isotope labeling of amino acids (pSILAC-AHA) in cell culture to quantify the newly synthesised host proteome during macrophage infection with the model intracellular bacterial pathogen, Salmonella enterica Typhimurium (STm). We monitored newly synthesised proteins across different host cell compartments and infection stages, and used available proteomics data in response to lipopolysaccharide to deconvolute the STm-specific response. Within this rich resource, we detected aberrant trafficking of lysosomal proteases to the extracellular space and the nucleus, the latter of which correlated with signatures of cell death. Pharmacological cathepsin inhibition suppressed Caspase-11 dependent macrophage cell death, thus demonstrating an active role for cathepsins during STm induced pyroptosis. Our study illustrates that resolving host proteome dynamics during infe...Continue Reading

Related Concepts

Bacterial Infections
Cathepsins
Cell Culture Techniques
Cell Death
Cell Nucleus
Extracellular Space
Isotope Labeling
Lipopolysaccharides
Macrophage Activation
Macrophage

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