The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease.
In response to infections and tissue damage, ASC-containing inflammasome protein complexes are assembled that promote caspase-1 activation, IL-1β and IL-18 processing and release, pyroptosis, and the release of ASC particles. However, excessive or persistent activation of the inflammasome causes inflammatory diseases. Therefore, a well-balanced inflammasome response is crucial for the maintenance of homeostasis. We show that the PYD-only protein POP1 inhibited ASC-dependent inflammasome assembly by preventing inflammasome nucleation, and consequently interfered with caspase-1 activation, IL-1β and IL-18 release, pyroptosis, and the release of ASC particles. There is no mouse ortholog for POP1, but transgenic expression of human POP1 in monocytes, macrophages, and dendritic cells protected mice from systemic inflammation triggered by molecular PAMPs, inflammasome component NLRP3 mutation, and ASC danger particles. POP1 expression was regulated by TLR and IL-1R signaling, and we propose that POP1 provides a regulatory feedback loop that shuts down excessive inflammatory responses and thereby prevents systemic inflammation.
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Lucia
L
de Almeida
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Sonal
S
Khare
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Alexander V
AV
Misharin
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Rajul
R
Patel
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Rojo A
RA
Ratsimandresy
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Melissa C
MC
Wallin
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Harris
H
Perlman
Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.
David R
DR
Greaves
Division of Rheumatology, Allergy, and Immunology, Department of Pediatrics, School of Medicine, University of California at San Diego (UCSD) and San Diego Branch, Ludwig Institute of Cancer Research, La Jolla, CA 92093, USA.
Hal M
HM
Hoffman
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: a-dorfleutner@northwestern.edu.
Andrea
A
Dorfleutner
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Interdepartmental Immunobiology Center and Skin Disease Research Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA. Electronic address: c-stehlik@northwestern.edu.
Christian
C
Stehlik
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D056587:Cryopyrin-Associated Periodic Syndromes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006706:Homeostasis; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology*; D055503:Protein Multimerization / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C490349:Pop1 protein, mouse; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D020170:Caspase 1