Mitochondrial ubiquitin ligase activator of NF-κB regulates NF-κB signaling in cells subjected to ER stress

Fujita,Hidetoshi; Aratani,Satoko; Fujii,Ryouji; Yamano,Yoshihisa; Yagishita,Naoko; Araya,Natsumi; Izumi,Toshihiko; Azakami,Kazuko; Hasegawa,Daisuke; Nishioka,Kusuki; Nakajima,Toshihiro

doi:10.3892/ijmm.2016.2566

Mitochondrial ubiquitin ligase activator of NF-κB regulates NF-κB signaling in cells subjected to ER stress

Authors:
- Hidetoshi Fujita
- Satoko Aratani
- Ryouji Fujii
- Yoshihisa Yamano
- Naoko Yagishita
- Natsumi Araya
- Toshihiko Izumi
- Kazuko Azakami
- Daisuke Hasegawa
- Kusuki Nishioka
- Toshihiro Nakajima
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Affiliations: Institute of Medical Science, Tokyo Medical University, Tokyo 160‑8402, Japan, Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan
Published online on: April 14, 2016 https://doi.org/10.3892/ijmm.2016.2566
Pages: 1611-1618

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Abstract

The nuclear factor-κB (NF-κB) transcription factor family members control various biological processes, such as apoptosis and proliferation. The endoplasmic reticulum (ER) has emerged as a major site of cellular homeostasis regulation. The accumulation of misfolded protein in the ER causes stress and ER stress-induced NF-κB activation to protect cells from apoptosis. In this study, we found a putative ER stress-response element (ERSE) on the promoter of mitochondrial ubiquitin ligase activator of NF-κB (MULAN), and that MULAN expression was upregulated by ER stress. MULAN specifically activated NF-κB dependent gene expression in an E3 ligase activity-dependent manner. The ectopic expression of MULAN induced the nuclear translocation of endogenous p65 and the degradation of IκB. Binding assay revealed that MULAN was associated with transforming growth factor β-activated kinase (TAK1). The knockdown of MULAN using siRNA inhibited the activation of NF-κB in the cells subjected to ER stress. The findings of our study indicate that MULAN is an E3 ligase that regulates NF-κB activation to protect cells from ER stress-induced apoptosis.

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