Polyubiquitinated Tristetraprolin protects from TNF-induced, Caspase-mediated Apoptosis [Signal Transduction]

July 23rd, 2014 by Resch, U., Cuapio, A., Sturtzel, C., Hofer, E., de Martin, R., Holper-Schichl, Y. M.

Binding of tumor necrosis factor (TNF) to its receptor (TNFR1) elicits the spatiotemporal assembly of two signaling complexes that coordinate the balance between cell survival and cell death. We have shown previously that following TNF treatment, the mRNA-decay protein Tristetraprolin (TTP) is K63-polyubiquitinated by TNF-receptor associated factor 2 (TRAF2), suggesting a regulatory role in TNFR signaling. Here, we demonstrate that TTP interacts with the TNFR1 in a TRAF2 dependent manner, thereby initiating the MEKK1/MKK4-dependent activation of c-Jun-N-terminal kinase (JNK) activities. This regulatory function towards JNK, but not NF-κB activation depends on TTPs lysine 105, which we identified as the corresponding TRAF2 ubiquitination site. Disabling TTP polyubiquitination results in enhanced TNF-induced apoptosis in cervical cancer cells. Together, we uncover a novel aspect of TNFR1 signaling, where TTP, in alliance with TRAF2, acts as balancer of JNK mediated cell survival versus death.