TY - JOUR
T1 - GLCCI1 is a novel protector against glucocorticoid-induced apoptosis in T cells
AU - Kiuchi, Zentaro
AU - Nishibori, Yukino
AU - Kutsuna, Satoru
AU - Kotani, Masashi
AU - Hada, Ichiro
AU - Kimura, Toru
AU - Fukutomi, Toshiyuki
AU - Fukuhara, Daisuke
AU - Ito-Nitta, Noriko
AU - Kudo, Akihiko
AU - Takata, Takanobu
AU - Ishigaki, Yasuhito
AU - Tomosugi, Naohisa
AU - Tanaka, Hirotoshi
AU - Matsushima, Satsuki
AU - Ogasawara, Shinya
AU - Hirayama, Yoshiaki
AU - Takematsu, Hiromu
AU - Yan, Kunimasa
N1 - Publisher Copyright:
© FASEB
PY - 2019/6/1
Y1 - 2019/6/1
N2 - 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.
AB - 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.
KW - LC8
KW - PAK1
KW - phosphorylation
UR - http://www.scopus.com/inward/record.url?scp=85067280098&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067280098&partnerID=8YFLogxK
U2 - 10.1096/fj.201800344RR
DO - 10.1096/fj.201800344RR
M3 - Article
C2 - 30860871
AN - SCOPUS:85067280098
SN - 0892-6638
VL - 33
SP - 7387
EP - 7402
JO - FASEB Journal
JF - FASEB Journal
IS - 6
ER -