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 Tago, Ken Yanagisawa, Tadashi Kasahara, Koichi Suzuki, Masafumi Takahashi

Research output: Contribution to journalArticle

15 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

Fingerprint

Inflammasomes
Macrophage Activation
Ubiquitination
Clustered Regularly Interspaced Short Palindromic Repeats
Caspase 1
Ubiquitin-Protein Ligases
Ubiquitin
Nucleotides
Macrophages
Apoptosis

ASJC Scopus subject areas

  • Immunology

Cite this

Kawashima, A., Karasawa, T., Tago, K., Kimura, H., Kamata, R., Usui-Kawanishi, F., ... 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

ARIH2 ubiquitinates NLRP3 and negatively regulates NLRP3 inflammasome activation in macrophages. / Kawashima, Akira; Karasawa, Tadayoshi; Tago, Kenji; Kimura, Hiroaki; Kamata, Ryo; Usui-Kawanishi, Fumitake; Watanabe, Sachiko; Ohta, Satoshi; Tago, Megumi; Yanagisawa, Ken; Kasahara, Tadashi; Suzuki, Koichi; Takahashi, Masafumi.

In: Journal of Immunology, Vol. 199, No. 10, 15.11.2017, p. 3614-3622.

Research output: Contribution to journalArticle

Kawashima, A, Karasawa, T, Tago, K, Kimura, H, Kamata, R, Usui-Kawanishi, F, Watanabe, S, Ohta, S, 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, vol. 199, no. 10, pp. 3614-3622. https://doi.org/10.4049/jimmunol.1700184
Kawashima A, Karasawa T, Tago K, Kimura H, Kamata R, Usui-Kawanishi F et al. ARIH2 ubiquitinates NLRP3 and negatively regulates NLRP3 inflammasome activation in macrophages. Journal of Immunology. 2017 Nov 15;199(10):3614-3622. https://doi.org/10.4049/jimmunol.1700184
Kawashima, Akira ; Karasawa, Tadayoshi ; Tago, Kenji ; Kimura, Hiroaki ; Kamata, Ryo ; Usui-Kawanishi, Fumitake ; Watanabe, Sachiko ; Ohta, Satoshi ; Tago, Megumi ; Yanagisawa, Ken ; Kasahara, Tadashi ; Suzuki, Koichi ; Takahashi, Masafumi. / ARIH2 ubiquitinates NLRP3 and negatively regulates NLRP3 inflammasome activation in macrophages. In: Journal of Immunology. 2017 ; Vol. 199, No. 10. pp. 3614-3622.
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