TY - JOUR
T1 - Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes
AU - Walch, Michael
AU - Dotiwala, Farokh
AU - Mulik, Sachin
AU - Thiery, Jerome
AU - Kirchhausen, Tomas
AU - Clayberger, Carol
AU - Krensky, Alan M.
AU - Martinvalet, Denis
AU - Lieberman, Judy
N1 - Funding Information:
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.
PY - 2014/6/5
Y1 - 2014/6/5
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2014.03.062
DO - 10.1016/j.cell.2014.03.062
M3 - Article
C2 - 24906149
AN - SCOPUS:84902108865
SN - 0092-8674
VL - 157
SP - 1309
EP - 1323
JO - Cell
JF - Cell
IS - 6
ER -