TBL2 is a novel PERK-binding protein that modulates stress-signaling and cell survival during endoplasmic reticulum stress.
Under ER stress, PKR-like ER-resident kinase (PERK) phosphorylates translation initiation factor eIF2α, resulting in repression of global protein synthesis and concomitant upregulation of the translation of specific mRNAs such as activating transcription factor 4 (ATF4). This PERK function is important for cell survival under ER stress and poor nutrient conditions. However, mechanisms of the PERK signaling pathway are not thoroughly understood. Here we identify transducin (beta)-like 2 (TBL2) as a novel PERK-binding protein. We found that TBL2 is an ER-localized type-I transmembrane protein and preferentially binds to the phosphorylated form of PERK, but not another eIF2α kinase GCN2 or ER-resident kinase IRE1, under ER stress. Immunoprecipitation analysis using various deletion mutants revealed that TBL2 interacts with PERK via the N-terminus proximal region and also associates with eIF2α via the WD40 domain. In addition, TBL2 knockdown can lead to impaired ATF4 induction under ER stress or poor nutrient conditions such as glucose and oxygen deprivation. Consistently, TBL2 knockdown rendered cells vulnerable to stresses similarly to PERK knockdown. Thus, TBL2 serves as a potential regulator of the PERK pathway.
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
Yoshinori
Y
Tsukumo
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
Satomi
S
Tsukahara
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
Aki
A
Furuno
Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan.
Shun-ichiro
S
Iemura
Biomedicinal Information Research Center, National Institute of Advanced Industrial Science and Technology, Koto-ku, Tokyo, Japan.
Toru
T
Natsume
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan.
Akihiro
A
Tomida
D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D057809:HEK293 Cells; D006801:Humans; D010100:Oxygen / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
C497109:ATF4 protein, human; D015852:Eukaryotic Initiation Factor-2; D034741:RNA, Small Interfering; C402405:TBL2 protein, human; D051701:Activating Transcription Factor 4; C460640:EIF2AK3 protein, human; C529271:EIF2AK4 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases; D019204:GTP-Binding Proteins; D005947:Glucose; D010100:Oxygen