title: Mitochondrial ubiquitin ligase activator of NF-κB regulates NF-κB signaling in cells subjected to ER stress.
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.
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Tokyo 160‑8402, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Tokyo 160‑8402, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Aratani
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan.
authors.forename: Ryouji
authors.initials: R
authors.lastname: Fujii
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Yamano
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Yagishita
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan.
authors.forename: Natsumi
authors.initials: N
authors.lastname: Araya
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Azakami
authors.affiliation: Institute of Medical Science, St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hasegawa
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Tokyo 160‑8402, Japan.
authors.forename: Kusuki
authors.initials: K
authors.lastname: Nishioka
authors.affiliation: Institute of Medical Science, Tokyo Medical University, Tokyo 160‑8402, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D014415:Tunicamycin; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7; C529067:MUL1 protein, human