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

• Published in: The FASEB journal 2019-06, Vol.33 (6), p.7387-7402
• Main Authors: Kiuchi, Zentaro, Nishibori, Yukino, Kutsuna, Satoru, Kotani, Masashi, Hada, Ichiro, Kimura, Toru, Fukutomi, Toshiyuki, Fukuhara, Daisuke, Ito-Nitta, Noriko, Kudo, Akihiko, Takata, Takanobu, Ishigaki, Yasuhito, Tomosugi, Naohisa, Tanaka, Hirotoshi, Matsushima, Satsuki, Ogasawara, Shinya, Hirayama, Yoshiaki, Takematsu, Hiromu, Yan, Kunimasa
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Apoptosis - drug effects; Apoptosis - physiology; Bcl-2-Like Protein 11 - biosynthesis; Bcl-2-Like Protein 11 - genetics; Cell Line; Cytoplasmic Dyneins - metabolism; Dimerization; Down-Regulation; Gene Knockdown Techniques; Glucocorticoids - pharmacology; Glucocorticoids - physiology; Humans; Hypertrophy; LC8; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubules - metabolism; p21-Activated Kinases - metabolism; PAK1; Phosphorylation; Protein Interaction Mapping; Protein Processing, Post-Translational; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - physiology; Recombinant Proteins - metabolism; RNA Interference; RNA, Small Interfering - genetics; RNA, Small Interfering - pharmacology; Sequence Alignment; Sequence Homology, Amino Acid; Signal Transduction - physiology; T-Lymphocytes - cytology; Thymus Gland - pathology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201800344RR

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