A Salmonella protein causes macrophage cell death by inducing autophagy.
Salmonella enterica, the causative agent of food poisoning and typhoid fever, induces programmed cell death in macrophages, a process found to be dependent on a type III protein secretion system, and SipB, a protein with membrane fusion activity that is delivered into host cells by this system. When expressed in cultured cells, SipB caused the formation of and localized to unusual multimembrane structures. These structures resembled autophagosomes and contained both mitochondrial and endoplasmic reticulum markers. A mutant form of SipB devoid of membrane fusion activity localized to mitochondria, but did not induce the formation of membrane structures. Upon Salmonella infection of macrophages, SipB was found in mitochondria, which appeared swollen and devoid of christae. Salmonella-infected macrophages exhibited marked accumulation of autophagic vesicles. We propose that Salmonella, through the action of SipB, kills macrophages by disrupting mitochondria, thereby inducing autophagy and cell death.
Hernandez
Lorraine D
LD
Section of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT 06510, USA.
Pypaert
Marc
M
Flavell
Richard A
RA
Galán
Jorge E
JE
D000818:Animals; D001343:Autophagy / Q000502:physiology*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012486:Salmonella typhimurium / Q000378:metabolism* / Q000472:pathogenicity
D001426:Bacterial Proteins; D008565:Membrane Proteins; D011993:Recombinant Fusion Proteins; C419942:Spi1 protein, Salmonella; C094579:invasion protein B, Salmonella typhimurium; D020170:Caspase 1