title: Positive Regulation of Interleukin-2 Expression by a Pseudokinase, Tribbles 1, in Activated T Cells.
abstract: Tribbles 1 (TRB1), a member of the Tribbles family, is a pseudokinase that is conserved among species and implicated in various human diseases including leukemia, cardiovascular diseases, and metabolic disorders. However, the role of TRB1 in the immune response is not understood. To evaluate this role, we examined regulation of TRB1 expression and the function of TRB1 in interleukin-2 (IL-2) induction in Jurkat cells, a human acute T cell leukemia cell line. We found that TRB1 was strongly induced by phorbol 12-myristate 13-acetate (PMA) and ionomycin in these cells. IL-2 expression was induced in Jurkat cells activated by PMA and ionomycin; however, knockdown of TRB1 resulted in decreased induction of IL-2. TRB1 null Jurkat cells established using the CRISPR/Cas9 system also showed reduction of IL-2 expression on PMA/ionomycin stimulation. TRB1 knockdown also markedly inhibited IL-2 promoter activation. To determine the mechanism of the stimulatory effect on IL-2 induction, we focused on histone deacetylases (HDACs), and found that HDAC1 preferentially interacts with TRB1. TRB1 suppressed the interaction of HDAC1 with nuclear factor of activated T cells 2 (NFAT2), which is a crucial transcription factor for IL-2 induction. These results indicate that TRB1 is a positive regulator of IL-2 induction in activated T cells.
authors.affiliation: Department of Cell Signaling, Graduate School of Pharmaceutical Sciences, Nagoya City University.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Miyajima
authors.forename: Yuka
authors.initials: Y
authors.lastname: Itoh
authors.forename: Yasumichi
authors.initials: Y
authors.lastname: Inoue
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
mesh_terms: D061207:Calcium Ionophores / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D061207:Calcium Ionophores; D002273:Carcinogens; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C493170:TRIB1 protein, human; D015759:Ionomycin; D017346:Protein Serine-Threonine Kinases; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D013755:Tetradecanoylphorbol Acetate