Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/cryopyrin/NLRP3 and ASC.
Cryopyrin (CIAS1, NLRP3) and ASC are components of the inflammasome, a multiprotein complex required for caspase-1 activation and cytokine IL-1beta production. CIAS1 mutations underlie autoinflammation characterized by excessive IL-1beta secretion. Disease-associated cryopyrin also causes a program of necrosis-like cell death in macrophages, the mechanistic details of which are unknown. We find that patient monocytes carrying disease-associated CIAS1 mutations exhibit excessive necrosis-like death by a process dependent on ASC and cathepsin B, resulting in spillage of the proinflammatory mediator HMGB1. Shigella flexneri infection also causes cryopyrin-dependent macrophage necrosis with features similar to the death caused by mutant CIAS1. This necrotic death is independent of caspase-1 and IL-1beta, and thus independent of the inflammasome. Furthermore, necrosis of primary macrophages requires the presence of Shigella virulence genes. While similar proteins mediate pathogen-induced cell death in plants, this report identifies cryopyrin as an important host regulator of programmed pathogen-induced necrosis in animals, a process we term pyronecrosis.
Willingham
Stephen B
SB
Lineberger Comprehensive Cancer Center, Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bergstralh
Daniel T
DT
O'Connor
William
W
Morrison
Amy C
AC
Taxman
Debra J
DJ
Duncan
Joseph A
JA
Barnoy
Shoshana
S
Venkatesan
Malabi M
MM
Flavell
Richard A
RA
Deshmukh
Mohanish
M
Hoffman
Hal M
HM
Ting
Jenny P-Y
JP
D000328:Adult; D000368:Aged; D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology; D002403:Cathepsins / Q000502:physiology; D016923:Cell Death / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000276:immunology*; D005260:Female; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000276:immunology; D008264:Macrophages / Q000382:microbiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012763:Shigella flexneri / Q000235:genetics / Q000472:pathogenicity*; D037521:Virulence Factors / Q000235:genetics
D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D024243:HMGB1 Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D037521:Virulence Factors; D002403:Cathepsins; D020170:Caspase 1