Proteomics

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


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 so they can survive and proliferate. To gain insight into this dynamic interface, we combined click-chemistry with pulsed stable isotope labelling of amino acids (pSILAC-AHA) and quantified the newly synthesised host proteome during macrophage infection with the model intracellular bacterial pathogen, Salmonella enterica Typhimurium (STm). We monitored newly synthesized proteins across different compartments and during different infection stages, and used available proteomics data in response to LPS to deconvolute the STm-specific response. Within this rich resource, we detect aberrant trafficking of lysosomal proteases to the extracellular space and the nucleus, the latter of which correlates 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 the utility of resolving the host proteome dynamics during infection to drive the discovery of novel biological mechanisms at the host-microbe interface.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Salmonella Enterica Mus Musculus (mouse)

TISSUE(S): B Cell, Cell Culture

SUBMITTER: Sophia Foehr  

LAB HEAD: Jeroen Krijgsveld

PROVIDER: PXD010179 | Pride | 2020-01-24

REPOSITORIES: Pride

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The interplay between host and pathogen relies heavily on rapid protein synthesis and accurate protein targeting to ensure pathogen destruction. To gain insight into this dynamic interface, we combined Click chemistry with pulsed stable isotope labelling of amino acids in cell culture to quantify the host proteome response during macrophage infection with the intracellular bacterial pathogen Salmonella enterica Typhimurium. We monitored newly synthesized proteins across different host cell compa  ...[more]

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