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

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...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Selkrig, Joel, Li, Nan, Bobonis, Jacob, Hausmann, Annika, Sueki, Anna, Imamura, Haruna, Bachir El Debs, Sigismondo, Gianluca, Florea, Bogdan, Overkleeft, Herman, Beltrao, Pedro, Wolf-Dietrich Hardt, Krijgsveld, Jeroen, Typas, Athanasios
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 07.11.2018
Subjects
Apoptosis
Bacterial infections
Caspase
Caspase-11
Cathepsins
Cell culture
Cell death
Infections
Lipopolysaccharides
Macrophages
Pathogens
Protein biosynthesis
Proteomics
Pyroptosis
Online AccessGet full text

Cover

More Information
Summary: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 infection can drive the discovery of biological mechanisms at the host-microbe interface.
DOI:10.1101/455048