TY  - JOUR
AU  - Stutz, Andrea
AU  - Kolbe, Carl-Christian
AU  - Stahl, Rainer
AU  - Horvath, Gabor L
AU  - Franklin, Bernardo S
AU  - van Ray, Olivia
AU  - Brinkschulte, Rebecca
AU  - Geyer, Matthias
AU  - Meissner, Felix
AU  - Latz, Eicke
TI  - NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain.
JO  - Journal of experimental medicine
VL  - 214
IS  - 6
SN  - 0022-1007
CY  - New York, NY
PB  - Rockefeller Univ. Press
M1  - DZNE-2020-05631
SP  - 1725-1736
PY  - 2017
AB  - 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.
KW  - Amino Acid Sequence
KW  - Animals
KW  - HEK293 Cells
KW  - Humans
KW  - Inflammasomes: metabolism
KW  - Mice
KW  - Models, Biological
KW  - Models, Molecular
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: chemistry
KW  - NLR Family, Pyrin Domain-Containing 3 Protein: metabolism
KW  - Phosphorylation
KW  - Phosphoserine: metabolism
KW  - Protein Binding
KW  - Protein Domains
KW  - Protein Phosphatase 2: metabolism
KW  - Pyrin: chemistry
KW  - Structure-Activity Relationship
KW  - Inflammasomes (NLM Chemicals)
KW  - NLR Family, Pyrin Domain-Containing 3 Protein (NLM Chemicals)
KW  - Nlrp3 protein, mouse (NLM Chemicals)
KW  - Pyrin (NLM Chemicals)
KW  - Phosphoserine (NLM Chemicals)
KW  - Protein Phosphatase 2 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28465465
C2  - pmc:PMC5460996
DO  - DOI:10.1084/jem.20160933
UR  - https://pub.dzne.de/record/139309
ER  -