TY - JOUR
T1 - Gliotoxin suppresses NF-κB activation by selectively inhibiting linear ubiquitin chain assembly complex (LUBAC)
AU - Sakamoto, Hiroki
AU - Egashira, Shinichiro
AU - Saito, Nae
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
N1 - Publisher Copyright:
© 2014 American Chemical Society.
PY - 2015/3/20
Y1 - 2015/3/20
N2 - 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.
AB - 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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U2 - 10.1021/cb500653y
DO - 10.1021/cb500653y
M3 - Article
C2 - 25494483
AN - SCOPUS:84925596826
VL - 10
SP - 675
EP - 681
JO - ACS Chemical Biology
JF - ACS Chemical Biology
SN - 1554-8929
IS - 3
ER -