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  NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain

Stutz, A., Kolbe, C., Stahl, R., Franklin, B. S., van Ray, O., Brinkschulte, R., et al. (2017). NLRP3 inflammasome assembly is regulated by phosphorylation of the pyrin domain. Journal of Experimental Medicine, 214(6), 1725-1736. doi:10.1084/jem.20160933.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-002D-8BF2-6 Version Permalink: https://hdl.handle.net/21.11116/0000-0008-8398-8
Genre: Journal Article

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http://jem.rupress.org/content/214/6/1725.long (Publisher version)
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 Creators:
Stutz, A., Author
Kolbe, C.C., Author
Stahl, R., Author
Franklin, B. S., Author
van Ray, O., Author
Brinkschulte, Rebecca1, Author
Geyer, Matthias1, Author
Meissner, F., Author
Latz, E., Author
Affiliations:
1Center of Advanced European Studies and Research (caesar), Max Planck Society, Ludwig-Erhard-Allee 2, 53175 Bonn, DE, ou_2173675              

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 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.

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Language(s): eng - English
 Dates: 2017-05-02
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1084/jem.20160933
 Degree: -

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Title: Journal of Experimental Medicine
  Abbreviation : J Exp Med
Source Genre: Journal
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Publ. Info: Baltimore, Md. : Rockefeller Institute for Medical Research
Pages: - Volume / Issue: 214 (6) Sequence Number: - Start / End Page: 1725 - 1736 Identifier: ISSN: 0022-1007
CoNE: https://pure.mpg.de/cone/journals/resource/954925413886