ARIH2 ubiquitinates NLRP3 and negatively regulates NLRP3 inflammasome activation in macrophages

Akira Kawashima, Tadayoshi Karasawa, Kenji Tago, Hiroaki Kimura, Ryo Kamata, Fumitake Usui-Kawanishi, Sachiko Watanabe, Satoshi Ohta, Megumi Funakoshi-Tago, Ken Yanagisawa, Tadashi Kasahara, Koichi Suzuki, Masafumi Takahashi

Research output: Contribution to journalArticle

35 Citations (Scopus)

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-1b 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-1b processing, and IL-1b 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.

Original languageEnglish
Pages (from-to)3614-3622
Number of pages9
JournalJournal of Immunology
Volume199
Issue number10
DOIs
Publication statusPublished - 2017 Nov 15

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    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. (2017). ARIH2 ubiquitinates NLRP3 and negatively regulates NLRP3 inflammasome activation in macrophages. Journal of Immunology, 199(10), 3614-3622. https://doi.org/10.4049/jimmunol.1700184