ZBTB24 regulates the apoptosis of human T cells via CDCA7/TRAIL-receptor axis

• Published in: Biochemical and biophysical research communications Vol. 514; no. 1; pp. 259 - 265
• Main Authors: Qin, Xiao-Yuan, Feng, Jing, Chen, Ge, Dou, Xun-Wu, Dai, Xiao-Qiu, Dong, Hong-Liang, Gong, Fang-Yuan, Xiao, Fei, Zhao, Ying, Gao, Xiao-Ming, Wang, Jun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.06.2019
• Subjects: CDCA7; Primary immunodeficiency; T-cell apoptosis; TRAIL; ZBTB24; TRAIL; ZBTB24; T-cell apoptosis; MOI; CDCA7; ICF; rmTRAIL-R2; Primary immunodeficiency
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.04.147

Mutations in ZBTB24 and CDCA7 cause the Immunodeficiency, Centromeric Instability and Facial Anomalies syndrome type 2 and 3 (ICF2/3), respectively. Most ICF2 patients carry ZBTB24 nonsense mutations and are thus ZBTB24-deficient. Although the immune deficiency in ICF2 patients is primarily regarded as a B-cell defect due to the greatly reduced serum antibodies and circulating memory B cells, the reduced expansions of PBMCs stimulated by mitogens or recall antigens suggest a T-cell defect in these patients as well. However, the molecular mechanisms behind this T-cell dysfunction remain unknown. In the present study, we demonstrated that ZBTB24-deficiency significantly represses the proliferation of human T cells by promoting TRAIL-induced cell death. Downregulation of ZBTB24 in both Jurkat and human primary T cells upregulates the expression of TRAIL and/or its death receptors (TRAIL-R1/2), and induces significant amount of cells to undergo apoptosis. The profound survival defects of ZBTB24-deficient cells are largely reversed by blocking TRAIL/TRAIL-R interactions with exogenous recombinant TRAIL-R2. Moreover, ZBTB24-downregulation reduces the expression of CDCA7, and knockdown of the latter in human T cells results in a phenotype resembling that caused by ZBTB24-depletion. Functionally, overexpression of CDCA7 abrogates the increased apoptosis in ZBTB24-depleted Jurkat T cells. Together, these data indicated that ZBTB24 regulates human T-cell apoptosis via CDCA7/TRAIL-R axis. Our study thus not only provides a molecular explanation for the T-cell defects in ZBTB24-deficient ICF2 patients, but also highlights a convergence between ZBTB24 and CDCA7, the two ICF genes, in modulating the functions of T cells. •Knockdown of ZBTB24 or CDCA7 upregulates TRAIL & TRAIL-Rs in human T cells.•Blocking TRAIL-signaling abrogates apoptosis induced by ZBTB24/CDCA7-depletions.•ZBTB24 activates the expression of CDCA7 in T cells.•Overexpression of CDCA7 reverses the survival defects caused by ZBTB24-depletions.