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
|
Resource |
DNA material |
CS-CA-MCS (RDB05963) |