title: TBL2 Associates With ATF4 mRNA Via Its WD40 Domain and Regulates Its Translation During ER Stress.
abstract: PKR-like ER-resident kinase (PERK) phosphorylates eukaryotic translation initiation factor 2 α (eIF2α) under endoplasmic reticulum (ER) stress; this results in repression of general translation and induction of specific gene expression, such as activating transcription factor 4 (ATF4). We previously showed that, upon ER stress, transducin (β)-like 2 (TBL2) was an ER-localized transmembrane protein and interacted with PERK and that TBL2 was involved in ATF4 expression and cell survival. Here, we show that TBL2 is able to associate with ATF4 mRNA and regulate its translation. The RNA-immunoprecipitation analysis using several TBL2 deletion mutants revealed that the WD40 domain was essential for association with ATF4 mRNA. Importantly, suppression of TBL2 by knockdown or overexpression of the TBL2 mutant with a defective WD40 domain diminished ATF4 induction at the translational level. Thus, our findings indicate that, under ER stress, TBL2 participates in ATF4 translation through its association with the mRNA.
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsukumo
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Tsukahara
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Furuno
authors.affiliation: Innovative Drug Development TR Section, Fukushima Medical University, Fukushima City, Fukushima, 960-1295, Japan.
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Iemura
authors.affiliation: Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo 135-0064, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Tomida
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D019204:GTP-Binding Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D011485:Protein Binding; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C497109:ATF4 protein, human; D012333:RNA, Messenger; C402405:TBL2 protein, human; D051701:Activating Transcription Factor 4; D019204:GTP-Binding Proteins
keywords: ATF4; ER stress; PERK