Abstract
Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates downstream JNK and p38 mitogen-activated protein kinase (MAPK) to relay death signals into cells in response to various environmental stress. However, whether ASK1 plays a role in T cell receptor (TCR)-mediated apoptosis of thymocytes is unclear. Here, we show 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 Akt upon TCR stimulation. Thus, our results identify a previously unappreciated signaling mechanism involving ASK1 in TCR-mediated apoptosis of thymocytes.
Highlights
The T cell receptor (TCR) on thymocytes balances sensitivity and specificity in recognizing self-peptide and major histocompatibility complex during the process of positive and negative selection in developing T cells [1,2]
As a ubiquitously expressed MAP3K, Apoptosis signal-regulating kinase 1 (ASK1) is essential for stress-induced apoptosis by relaying upstream signals via MKK4/MKK7-JNK and MKK3/MAPK kinase 6 (MKK6)-p38 mitogen-activated protein kinase (MAPK) pathways to activate the apoptotic machineries in various cell types under different stress conditions [15]
Our study further reveals that Akt acts upstream, with the help of Fas inhibitory molecule (FAIM), to dampen the activation of ASK1-JNK/p38 signaling pathways
Summary
The T cell receptor (TCR) on thymocytes balances sensitivity and specificity in recognizing self-peptide and major histocompatibility complex (self-pMHC) during the process of positive and negative selection in developing T cells [1,2]. Thymocytes with TCR of low- or moderate- affinity for self-pMHC receive survival signals and are positively selected. Thymocytes expressing high-affinity TCRs for self-pMHC are eliminated through TCR-mediated apoptosis. This process is crucial in establishing the central tolerance of T cells [3,4]. Complex intracellular signaling pathways are involved in this process to convey signals from the TCR to trigger the cell death machinery that results in the apoptosis of thymocytes [5,6].
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