GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells

Zentaro Kiuchi, Yukino Nishibori, Satoru Kutsuna, Masashi Kotani, Ichiro Hada, Toru Kimura, Toshiyuki Fukutomi, Daisuke Fukuhara, Noriko Ito-Nitta, Akihiko Kudo, Takanobu Takata, Yasuhito Ishigaki, Naohisa Tomosugi, Hirotoshi Tanaka, Satsuki Matsushima, Shinya Ogasawara, Yoshiaki Hirayama, Hiromu Takematsu, Kunimasa Yan

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Abstract

Glucocorticoids (GCs) potently induce T-cell apoptosis in a GC receptor (GR)-dependent manner and are used to control lymphocyte function in clinical practice. However, its downstream pathways remain controversial. Here, we showed that GC-induced transcript 1 (GLCCI1) is a novel downstream molecule of the GC-GR cascade that acts as an antiapoptotic mediator in thymic T cells. GLCCI1 was highly phosphorylated and colocalized with microtubules in GLCCI1-transfected human embryonic kidney QBI293A cells. GR-dependent up-regulation of GLCCI1 was associated with GC-induced proapoptotic events in a cultured thymocyte cell line. However, GLCCI1 knockdown in a thymocyte cell line led to apoptosis. Consistently, transgenic mice overexpressing human GLCCI1 displayed enlarged thymi that consisted of larger numbers of thymocytes. Further molecular characterization showed that GLCCI1 bound to both dynein light chain LC8-type 1 (LC8) and its functional kinase, p21-protein activated kinase 1 (PAK1), thereby inhibiting the kinase activity of PAK1 toward LC8 phosphorylation, a crucial event in apoptotic signaling. GLCCI1 induction facilitated LC8 dimer formation and reduced Bim expression. Thus, GLCCI1 is a candidate factor involved in apoptosis regulation of thymic T cells.—Kiuchi, Z., Nishibori, Y., Kutsuna, S., Kotani, M., Hada, I., Kimura, T., Fukutomi, T., Fukuhara, D., Ito-Nitta, N., Kudo, A., Takata, T., Ishigaki, Y., Tomosugi, N., Tanaka, H., Matsushima, S., Ogasawara, S., Hirayama, Y., Takematsu, H., Yan, K. GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells. FASEB J. 33, 7387–7402 (2019). www.fasebj.org.

Original languageEnglish
Pages (from-to)7387-7402
Number of pages16
JournalFASEB Journal
Volume33
Issue number6
DOIs
Publication statusPublished - 01-06-2019

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Kiuchi, Z., Nishibori, Y., Kutsuna, S., Kotani, M., Hada, I., Kimura, T., Fukutomi, T., Fukuhara, D., Ito-Nitta, N., Kudo, A., Takata, T., Ishigaki, Y., Tomosugi, N., Tanaka, H., Matsushima, S., Ogasawara, S., Hirayama, Y., Takematsu, H., & Yan, K. (2019). GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells. FASEB Journal, 33(6), 7387-7402. https://doi.org/10.1096/fj.201800344RR