Membrane damage during Listeria monocytogenes infection triggers a caspase-7 dependent cytoprotective response.
The cysteine protease caspase-7 has an established role in the execution of apoptotic cell death, but recent findings also suggest involvement of caspase-7 during the host response to microbial infection. Caspase-7 can be cleaved by the inflammatory caspase, caspase-1, and has been implicated in processing and activation of microbial virulence factors. Thus, caspase-7 function during microbial infection may be complex, and its role in infection and immunity has yet to be fully elucidated. Here we demonstrate that caspase-7 is cleaved during cytosolic infection with the intracellular bacterial pathogen, Listeria monocytogenes. Cleavage of caspase-7 during L. monocytogenes infection did not require caspase-1 or key adaptors of the primary pathways of innate immune signaling in this infection, ASC, RIP2 and MyD88. Caspase-7 protected infected macrophages against plasma membrane damage attributable to the bacterial pore-forming toxin Listeriolysin O (LLO). LLO-mediated membrane damage could itself trigger caspase-7 cleavage, independently of infection or overt cell death. We also detected caspase-7 cleavage upon treatment with other bacterial pore-forming toxins, but not in response to detergents. Taken together, our results support a model where cleavage of caspase-7 is a consequence of toxin-mediated membrane damage, a common occurrence during infection. We propose that host activation of caspase-7 in response to pore formation represents an adaptive mechanism by which host cells can protect membrane integrity during infection.
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.
Sara K B
SK
Cassidy
Jon A
JA
Hagar
Thirumala Devi
TD
Kanneganti
Luigi
L
Franchi
Gabriel
G
Nuñez
Mary X D
MX
O'Riordan
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D020170:Caspase 1 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism*; D002462:Cell Membrane / Q000382:microbiology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006460:Hemolysin Proteins / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology / Q000378:metabolism / Q000472:pathogenicity*; D008088:Listeriosis / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D037521:Virulence Factors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C498534:Pycard protein, mouse; D037521:Virulence Factors; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D053179:Caspase 7; D020170:Caspase 1; C038705:hlyA protein, Listeria monocytogenes