From Left: Dr Huo Jianxin, Prof Lam Kong Peng, Dr Xu Shengli
Jianxin Huo 1, Shengli Xu 1,2 and Kong-Peng Lam 1,3,4
1 Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore
2 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4 School of Biological Sciences, Nanyang Technological University, Singapore
Published in Cells 2020 9(3): 585 (Online Version)
T lymphocytes (T cells) are generated in the thymus, where developing thymocytes must accept one of two fates: differentiation or programmed cell death (apoptosis). These fates are chiefly determined by signals that originate from the T cell receptor (TCR), a single receptor complex with a remarkable capacity to decide between the distinct cell fates. Understanding the logic of TCR signaling may eventually explain how thymocytes and T cells distinguish self from nonself.
Apoptosis signal-regulating kinase 1 (ASK1) is known as a mitogen-activated protein kinase kinase kinase (MAPKKK), a member of MAP kinase family. It activates downstream c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases to relay death signals into cells in response to various environmental stress. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases. However, whether ASK1 plays a role in TCR-mediated apoptosis of thymocytes is unclear.
Here, our study shows that ASK1 is activated upon TCR stimulation and plays an important role in TCR-mediated apoptosis of thymocytes by triggering downstream JNK and p38 signaling cascades. Mechanistically, ASK1-JNK/p38 signaling leads to the upregulation of neuron-derived clone 77 (Nur77), a critical pro-apoptotic protein involved in TCR-mediated apoptosis of thymocytes. Furthermore, we demonstrate that the activation of ASK1 is negatively modulated by survival kinase Akt upon TCR stimulation. Thus, our results identify a previously unappreciated signaling mechanism involving ASK1 in TCR-mediated apoptosis of thymocytes. Further research isneeded to define ASK1 networks altered in immune system disorders and uncover potential benefits of ASK1 inhibition as a therapeutic target.
Figure 1. Schematic representation of ASK1 signaling cascades in T cell receptor (TCR)-stimulated thymocyte. (1) Upon engagement of TCR, ASK1 is phosphorylated and further activates downstream JNK and p38 MAP kinases. (2) Nur77 expression is upregulated by TCR-ASK1-JNK/p38 signaling and required for caspase activation leading to apoptosis of thymocytes. (3) Survival kinase Akt is activated upon TCR stimulation in a FAIM-dependent manner and negatively regulates ASK1-JNK/p38-Nur77 signaling.