tailieunhanh - Báo cáo khoa học: An anthrax lethal factor mutant that is defective at causing pyroptosis retains proapoptotic activity

Anthrax lethal toxin triggers death in some cell types, such as macrophages, and causes a variety of cellular dysfunctions in others. Collectively, these effects dampen the innate and adaptive immune systems to allowBacillus anthracis to survive and proliferate in the mammalian host. | ỊFEBS Journal An anthrax lethal factor mutant that is defective at causing pyroptosis retains proapoptotic activity Stephanie Ngai Sarah Batty Kuo-Chieh Liao and Jeremy Mogridge Department of Laboratory Medicine and Pathobiology University of Toronto Canada Keywords anthrax lethaltoxin MAPKK Nlrp1b Correspondence J. Mogridge Department of Laboratory Medicine and Pathobiology Medical Sciences Building Rm. 6308 1 King s College Circle University of Toronto Toronto ON Canada M5S 1A8 Fax 1 416 978 5959 Tel 1 416 946 8095 E-mail Received 31 July 2009 revised 29 September 2009 accepted 23 October 2009 doi Anthrax lethal toxin triggers death in some cell types such as macrophages and causes a variety of cellular dysfunctions in others. Collectively these effects dampen the innate and adaptive immune systems to allow Bacillus anthracis to survive and proliferate in the mammalian host. The diverse effects caused by the toxin have in part been attributed to its interference with signaling pathways in target cells. Lethal factor LF is the proteolytic component of the toxin and cleaves six members of the mitogen-activated protein kinase kinase family after being delivered to the cytosol by the cellbinding component of the toxin protective antigen. The effect of cleaving these mitogen-activated protein kinase kinases is to interfere with extracellular signal-related kinase ERK p38 and c-Jun N-terminal kinase signaling. Here we characterized an LF mutant LF-K518E E682G that was defective at causing pyroptosis in RAW cells and at activating the Nlrp1b inflammasome in a heterologous expression system. LF-K518E E682G did not exhibit an overall impairment of function however because it was able to downregulate the ERK pathway but not the p38 or c-Jun N-terminal kinase pathways. Furthermore LF-K518E E682G efficiently killed melanoma cells which were shown previously to undergo apoptosis in response to lethal toxin or