Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes

Michael Walch*, Farokh Dotiwala, Sachin Mulik, Jerome Thiery, Tomas Kirchhausen, Carol Clayberger, Alan M. Krensky, Denis Martinvalet, Judy Lieberman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

83 Scopus citations

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 languageEnglish (US)
Pages (from-to)1309-1323
Number of pages15
JournalCell
Volume157
Issue number6
DOIs
StatePublished - Jun 5 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Cytotoxic cells kill intracellular bacteria through granulysin-mediated delivery of granzymes'. Together they form a unique fingerprint.

Cite this