Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC)

Hiroki Sakamoto; Shinichiro Egashira; Nae Saito; Takayoshi Kirisako; Simon Miller; Yoshiteru Sasaki; Tadahiko Matsumoto; Manabu Shimonishi; Toru Komatsu; Takuya Terai; Tasuku Ueno; Kenjiro Hanaoka; Hirotatsu Kojima; Takayoshi Okabe; Soichi Wakatsuki; Kazuhiro Iwai; Tetsuo Nagano

doi:10.1021/cb500653y

Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC)

Hiroki Sakamoto, Shinichiro Egashira, Nae Saito, Takayoshi Kirisako, Simon Miller, Yoshiteru Sasaki, Tadahiko Matsumoto, Manabu Shimonishi, Toru Komatsu, Takuya Terai, Tasuku Ueno, Kenjiro Hanaoka, Hirotatsu Kojima, Takayoshi Okabe, Soichi Wakatsuki, Kazuhiro Iwai, Tetsuo Nagano

Research output: Contribution to journal › Article › peer-review

58 Citations (Scopus)

Abstract

A linear ubiquitin chain, which consists of ubiquitin molecules linked via their N- and C-termini, is formed by a linear ubiquitin chain assembly complex (LUBAC) composed of HOIP, HOIL-1L, and SHARPIN, and conjugation of a linear ubiquitin chain on the NF-κB essential modulator (NEMO) is deeply involved in NF-κB activation induced by various signals. Since abnormal activation of NF-κB is associated with inflammatory disease and malignancy, we searched for an inhibitor of LUBAC by high-throughput screening (HTS) with a Tb³⁺-fluorescein FRET system. As a result, we found that the fungal metabolite gliotoxin inhibits LUBAC selectively by binding to the RING-IBR-RING domain of HOIP, the catalytic center of LUBAC. Gliotoxin has been well-known as an inhibitor of NF-κB activation, though its action mechanism has remained elusive. Here, we show that gliotoxin inhibits signal-induced NF-κB activation by selectively inhibiting LUBAC-mediated linear ubiquitin chain formation.

Original language	English
Pages (from-to)	675-681
Number of pages	7
Journal	ACS chemical biology
Volume	10
Issue number	3
DOIs	https://doi.org/10.1021/cb500653y
Publication status	Published - 2015 Mar 20
Externally published	Yes

ASJC Scopus subject areas

Biochemistry
Molecular Medicine

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10.1021/cb500653y

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Sakamoto, H., Egashira, S., Saito, N., Kirisako, T., Miller, S., Sasaki, Y., Matsumoto, T., Shimonishi, M., Komatsu, T., Terai, T., Ueno, T., Hanaoka, K., Kojima, H., Okabe, T., Wakatsuki, S., Iwai, K., & Nagano, T. (2015). Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC). ACS chemical biology, 10(3), 675-681. https://doi.org/10.1021/cb500653y

Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC). / Sakamoto, Hiroki; Egashira, Shinichiro; Saito, Nae; Kirisako, Takayoshi; Miller, Simon; Sasaki, Yoshiteru; Matsumoto, Tadahiko; Shimonishi, Manabu; Komatsu, Toru; Terai, Takuya; Ueno, Tasuku; Hanaoka, Kenjiro; Kojima, Hirotatsu; Okabe, Takayoshi; Wakatsuki, Soichi; Iwai, Kazuhiro; Nagano, Tetsuo.

In: ACS chemical biology, Vol. 10, No. 3, 20.03.2015, p. 675-681.

Research output: Contribution to journal › Article › peer-review

Sakamoto, H, Egashira, S, Saito, N, Kirisako, T, Miller, S, Sasaki, Y, Matsumoto, T, Shimonishi, M, Komatsu, T, Terai, T, Ueno, T, Hanaoka, K, Kojima, H, Okabe, T, Wakatsuki, S, Iwai, K & Nagano, T 2015, 'Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC)', ACS chemical biology, vol. 10, no. 3, pp. 675-681. https://doi.org/10.1021/cb500653y

Sakamoto, Hiroki ; Egashira, Shinichiro ; Saito, Nae ; Kirisako, Takayoshi ; Miller, Simon ; Sasaki, Yoshiteru ; Matsumoto, Tadahiko ; Shimonishi, Manabu ; Komatsu, Toru ; Terai, Takuya ; Ueno, Tasuku ; Hanaoka, Kenjiro ; Kojima, Hirotatsu ; Okabe, Takayoshi ; Wakatsuki, Soichi ; Iwai, Kazuhiro ; Nagano, Tetsuo. / Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC). In: ACS chemical biology. 2015 ; Vol. 10, No. 3. pp. 675-681.

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title = "Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC)",

abstract = "A linear ubiquitin chain, which consists of ubiquitin molecules linked via their N- and C-termini, is formed by a linear ubiquitin chain assembly complex (LUBAC) composed of HOIP, HOIL-1L, and SHARPIN, and conjugation of a linear ubiquitin chain on the NF-κB essential modulator (NEMO) is deeply involved in NF-κB activation induced by various signals. Since abnormal activation of NF-κB is associated with inflammatory disease and malignancy, we searched for an inhibitor of LUBAC by high-throughput screening (HTS) with a Tb3+-fluorescein FRET system. As a result, we found that the fungal metabolite gliotoxin inhibits LUBAC selectively by binding to the RING-IBR-RING domain of HOIP, the catalytic center of LUBAC. Gliotoxin has been well-known as an inhibitor of NF-κB activation, though its action mechanism has remained elusive. Here, we show that gliotoxin inhibits signal-induced NF-κB activation by selectively inhibiting LUBAC-mediated linear ubiquitin chain formation.",

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AU - Sakamoto, Hiroki

AU - Egashira, Shinichiro

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AU - Kirisako, Takayoshi

AU - Miller, Simon

AU - Sasaki, Yoshiteru

AU - Matsumoto, Tadahiko

AU - Shimonishi, Manabu

AU - Komatsu, Toru

AU - Terai, Takuya

AU - Ueno, Tasuku

AU - Hanaoka, Kenjiro

AU - Kojima, Hirotatsu

AU - Okabe, Takayoshi

AU - Wakatsuki, Soichi

AU - Iwai, Kazuhiro

AU - Nagano, Tetsuo

PY - 2015/3/20

Y1 - 2015/3/20

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Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC)

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