Journal Article

DZNE-2020-05631

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain.

Stutz, A. ; Kolbe, C.-C. ; Stahl, R. ; Horvath, G. L. ; Franklin, B. S. ; van Ray, O. ; Brinkschulte, R. ; Geyer, M. ; Meissner, F. ; Latz, E. (Last author)DZNE*

2017
Rockefeller Univ. Press New York, NY

This record in other databases:    

Please use a persistent id in citations: doi:10.1084/jem.20160933

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.

Keyword(s): Amino Acid Sequence (MeSH) ; Animals (MeSH) ; HEK293 Cells (MeSH) ; Humans (MeSH) ; Inflammasomes: metabolism (MeSH) ; Mice (MeSH) ; Models, Biological (MeSH) ; Models, Molecular (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: chemistry (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; Phosphorylation (MeSH) ; Phosphoserine: metabolism (MeSH) ; Protein Binding (MeSH) ; Protein Domains (MeSH) ; Protein Phosphatase 2: metabolism (MeSH) ; Pyrin: chemistry (MeSH) ; Structure-Activity Relationship (MeSH) ; Inflammasomes ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nlrp3 protein, mouse ; Pyrin ; Phosphoserine ; Protein Phosphatase 2

---

Contributing Institute(s):

1. Innate Immunity in Neurodegeneration (AG Latz)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2017

---

Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; IF >= 15 ; JCR ; SCOPUS ; Web of Science Core Collection

---