Abstract
When killer lymphocytes recognize infected cells, perforin delivers cytotoxic proteases (granzymes) into the target cell to trigger apoptosis. What happens to intracellular bacteria during this process is unclear. Human, but not rodent, cytotoxic granules also contain granulysin, an antimicrobial peptide. Here, we show that granulysin delivers granzymes into bacteria to kill diverse bacterial strains. In Escherichia coli, granzymes cleave electron transport chain complex I and oxidative stress defense proteins, generating reactive oxygen species (ROS) that rapidly kill bacteria. ROS scavengers and bacterial antioxidant protein overexpression inhibit bacterial death. Bacteria overexpressing a GzmB-uncleavable mutant of the complex I subunit nuoF or strains that lack complex I still die, but more slowly, suggesting that granzymes disrupt multiple vital bacterial pathways. Mice expressing transgenic granulysin are better able to clear Listeria monocytogenes. Thus killer cells play an unexpected role in bacterial defense.
Original language | English (US) |
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Pages (from-to) | 1309-1323 |
Number of pages | 15 |
Journal | Cell |
Volume | 157 |
Issue number | 6 |
DOIs | |
State | Published - Jun 5 2014 |
Funding
This work was supported by NIH AI-045587 (to J.L.), the Stiefel-Zangger and the Kurt and Senta Herrmann Foundations (to M.W.), and PCMM-Glaxo Smith Kline Alliance (to F.D.), and by NIH grant GM-075252 (to T.K.). We thank Zhan Xu and Solange Kharoubi Hess for technical support, Luis Filgueira for helpful discussions, Marshall Thomas for HeLa-BCL2 cells, James Imlay (University of Illinois) for valuable suggestions and for the L106 E. coli strain, Susan Lovett (Brandeis) for the recA strain, Thorsten Friedrich (Albert-Ludwigs-University, Freiburg, Germany) for E. coli strain ANN0221/pBADnuo/His-nuoF, and Darren Higgins (Harvard Medical School) for the Lm expression plasmid pLIV1 and Eric Marino for maintaining the Imaging Resource used in this study.
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology