RRC ID 49558
Author Kawashima A, Karasawa T, Tago K, Kimura H, Kamata R, Usui-Kawanishi F, Watanabe S, Ohta S, Funakoshi-Tago M, Yanagisawa K, Kasahara T, Suzuki K, Takahashi M.
Title ARIH2 Ubiquitinates NLRP3 and Negatively Regulates NLRP3 Inflammasome Activation in Macrophages.
Journal J Immunol
Abstract The nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a molecular platform that induces caspase-1 activation and subsequent IL-1β maturation, and is implicated in inflammatory diseases; however, little is known about the negative regulation of NLRP3 inflammasome activation. In this article, we identified an E3 ligase, Ariadne homolog 2 (ARIH2), as a posttranslational negative regulator of NLRP3 inflammasome activity in macrophages. ARIH2 interacted with NLRP3 via its NACHT domain (aa 220-575) in the NLRP3 inflammasome complex. In particular, we found that while using mutants of ARIH2 and ubiquitin, the really interesting new gene 2 domain of ARIH2 was required for NLRP3 ubiquitination linked through K48 and K63. Deletion of endogenous ARIH2 using CRISPR/Cas9 genome editing inhibited NLRP3 ubiquitination and promoted NLRP3 inflammasome activation, resulting in apoptosis-associated speck-like protein containing a caspase recruitment domain oligomerization, pro-IL-1β processing, and IL-1β production. Conversely, ARIH2 overexpression promoted NLRP3 ubiquitination and inhibited NLRP3 inflammasome activation. Our findings reveal a novel mechanism of ubiquitination-dependent negative regulation of the NLRP3 inflammasome by ARIH2 and highlight ARIH2 as a potential therapeutic target for inflammatory diseases.
Volume 199(10)
Pages 3614-3622
Published 2017-11-15
DOI 10.4049/jimmunol.1700184
PII jimmunol.1700184
PMID 29021376
MeSH Animals Apoptosis Clustered Regularly Interspaced Short Palindromic Repeats HEK293 Cells Humans Inflammasomes / metabolism* Inflammation Interleukin-1beta / metabolism* Macrophages / immunology* Mice Mice, Inbred C57BL Mutation / genetics NLR Family, Pyrin Domain-Containing 3 Protein / metabolism* Protein Binding Protein Engineering Ubiquitin-Protein Ligases / genetics Ubiquitin-Protein Ligases / metabolism* Ubiquitination
IF 4.718
Times Cited 27
DNA material CS-CA-MCS (RDB05963)