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@ARTICLE{Stutz:139309,
author = {Stutz, Andrea and Kolbe, Carl-Christian and Stahl, Rainer
and Horvath, Gabor L and Franklin, Bernardo S and van Ray,
Olivia and Brinkschulte, Rebecca and Geyer, Matthias and
Meissner, Felix and Latz, Eicke},
title = {{NLRP}3 inflammasome assembly is regulated by
phosphorylation of the pyrin domain.},
journal = {Journal of experimental medicine},
volume = {214},
number = {6},
issn = {0022-1007},
address = {New York, NY},
publisher = {Rockefeller Univ. Press},
reportid = {DZNE-2020-05631},
pages = {1725-1736},
year = {2017},
abstract = {NLRP3 is a cytosolic pattern recognition receptor that
senses microbes and endogenous danger signals. Upon
activation, NLRP3 forms an inflammasome with the adapter
ASC, resulting in caspase-1 activation, release of
proinflammatory cytokines and cell death. How NLRP3
activation is regulated by transcriptional and
posttranslational mechanisms to prevent aberrant activation
remains incompletely understood. Here, we identify three
conserved phosphorylation sites in NLRP3 and demonstrate
that NLRP3 activation is controlled by phosphorylation of
its pyrin domain (PYD). Phosphomimetic residues in NLRP3 PYD
abrogate inflammasome activation and structural modeling
indicates that phosphorylation of the PYD regulates
charge-charge interaction between two PYDs that are
essential for NLRP3 activation. Phosphatase 2A (PP2A)
inhibition or knock-down drastically reduces NLRP3
activation, showing that PP2A can license inflammasome
assembly via dephosphorylating NLRP3 PYD. These results
propose that the balance between kinases and phosphatases
acting on the NLRP3 PYD is critical for NLRP3 activation.},
keywords = {Amino Acid Sequence / Animals / HEK293 Cells / Humans /
Inflammasomes: metabolism / Mice / Models, Biological /
Models, Molecular / NLR Family, Pyrin Domain-Containing 3
Protein: chemistry / NLR Family, Pyrin Domain-Containing 3
Protein: metabolism / Phosphorylation / Phosphoserine:
metabolism / Protein Binding / Protein Domains / Protein
Phosphatase 2: metabolism / Pyrin: chemistry /
Structure-Activity Relationship / Inflammasomes (NLM
Chemicals) / NLR Family, Pyrin Domain-Containing 3 Protein
(NLM Chemicals) / Nlrp3 protein, mouse (NLM Chemicals) /
Pyrin (NLM Chemicals) / Phosphoserine (NLM Chemicals) /
Protein Phosphatase 2 (NLM Chemicals)},
cin = {AG Latz},
ddc = {610},
cid = {I:(DE-2719)1013024},
pnm = {342 - Disease Mechanisms and Model Systems (POF3-342)},
pid = {G:(DE-HGF)POF3-342},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:28465465},
pmc = {pmc:PMC5460996},
doi = {10.1084/jem.20160933},
url = {https://pub.dzne.de/record/139309},
}