Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage
Name:
Publisher version
View Source
Access full-text PDFOpen Access
View Source
Check access options
Check access options
Authors
Bronner, Denise N.Abuaita, Basel H.
Chen, Xiaoyun
Fitzgerald, Katherine A
Nunez, Gabriel
He, Yongqun
Yin, Xiao-Ming
O'Riordan, Mary X. D
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2015-09-15Keywords
AnimalsBH3 Interacting Domain Death Agonist Protein
Blotting, Western
Brucella abortus
Carrier Proteins
Caspase 2
Cells, Cultured
DNA-Binding Proteins
Endoplasmic Reticulum Stress
Endoribonucleases
HEK293 Cells
Host-Pathogen Interactions
Humans
Inflammasomes
Interleukin-1beta
Macrophages
Mice, Inbred C57BL
Mice, Knockout
Mitochondria
Protein-Serine-Threonine Kinases
RNA Interference
Reactive Oxygen Species
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors
Immunity
Metadata
Show full item recordAbstract
Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1alpha ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1alpha activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2-dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity.Source
Immunity. 2015 Sep 15;43(3):451-62. doi: 10.1016/j.immuni.2015.08.008. Epub 2015 Sep 1. Link to article on publisher's siteDOI
10.1016/j.immuni.2015.08.008Permanent Link to this Item
http://hdl.handle.net/20.500.14038/30653PubMed ID
26341399Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.immuni.2015.08.008