ERK5 is involved in TCR‐induced apoptosis through the modification of Nur77

Abstract

Nur77 is a nuclear orphan steroid receptor that has been implicated in negative selection when immature T cells are strongly activated through interaction with self peptide‐MHC complexes. The expression of Nur77 in thymocytes and T cell lines leads to apoptosis in a manner dependent on its transcriptional activity. It is well established that Nur77 function is negatively regulated by post‐translational modification. Here we demonstrate that the MAPK‐induced phosphorylation of Nur77 during T cell activation plays a critical role in the induction of apoptosis. Upon T cell receptor (TCR) stimulation, ERK5 (also known as big MAP kinase 1, BMK1), a member of the MAPK family, phosphorylates Nur77, leading to its transcriptional activation. In contrast, the activation of the ERK2 signaling pathway failed to activate Nur77 although ERK2 is also able to phosphorylate Nur77. Furthermore, the blockade of ERK5 signaling pathway suppressed TCR‐induced cell death. These results indicate that ERK5 regulates Nur77 function through its phosphorylation.

Phosphorylation of Nur77 by the MEK-ERK-RSK Cascade Induces Mitochondrial Translocation and Apoptosis in T Cells

“…Most investigations of ERK1/2 MAPK in T cells used the MEK1 inhibitors PD98059 or U0126. Recent data question the specificity of these inhibitors and attributed their ability to inhibit apoptosis to inactivation of ERK5 which, in turn, was suggested to regulate Nur77 by either transcriptional or posttranslation modifications (16,18). However, these conclusions are contradicted by convincing genetic evidence.…”

“…Therefore, it possibly could be a candidate substrate for MAPKs. Consistent with this notion, it was reported recently that Nur77 is regulated by the ERK5 MAPK cascade either through transcriptional up-regulation or posttranslational modification mechanism in T cells (16,18). However, conditional ablation of ERK5 in T cells affects neither transcription of Nur77 nor T cell development in thymus (19), suggesting the role of the MAPK cascades in regulation of Nur77-mediated T cell apoptosis should be re-evaluated.…”

“…Although Cunningham et al (31) suggested that the ERK1/2 MAPK pathway phosphorylates Nur77 and modulates its intracellular translocation in peripheral T cells, these authors did not investigate physiological consequences of this phosphorylation. Similarly, Fujii et al (18) found that the ERK1/2 MAPK pathway can phosphorylate Nur77 both in vitro and in COS7 cells. Our studies extend these observations and demonstrate that phosphorylation of Nur77 by ERK1/2 MAPK cascade contributes to its killing activity in T cells (Figs.…”

TAK1–JNK Axis Mediates Survival Signal through Mcl1 Stabilization in Activated T Cells

“…CTLL-2 cells obtained from the American Type Culture Collection were maintained in RPMI 1640 medium containing 10% FCS, 55 mM 2-ME, 100 U/ml penicillin, 100 mg/ml streptomycin, MEM nonessential amino acids (Wako), 10 mM HEPES, and 1 mM sodium pyruvate supplemented with 50 U/ml human recombinant IL-2, and used as a model of T cell blasts. For DNA fragmentation analysis, genomic DNA was obtained and subjected to agarose gel electrophoresis (19).…”

Programmed Cell Death in T Cell Development

“…Characterization of the MEK5-ERK5 pathway is relatively recent compared to other MAPK signaling cascades. Dominant-negative ERK5 and MEK5 inhibit thymocyte apoptosis in vitro and peptide-induced deletion in some models of negative selection, respectively (Fujii et al 2008;Sohn et al 2008). While JNK, p38, and ERK5 have been implicated in negative selection, they are not required for positive selection of thymocytes (Rincon et al 1998;Sugawara et al 1998;Sohn et al 2008).…”