Role of Apoptosis Signal-regulating Kinase 1 (ASK1) as an activator of the GAPDH-Siah1 Stress-Signaling Cascade. [Cell Biology]

November 12th, 2014 by Tristan, C. A., Ramos, A., Shahani, N., Emiliani, F. E., Nakajima, H., Noeh, C. C., Kato, Y., Takeuchi, T., Noguchi, T., Kadowaki, H., Sedlak, T. W., Ishizuka, K., Ichijo, H., Sawa, A.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) plays roles in both energy maintenance, and stress signaling by forming a protein complex with seven in absentia homolog 1 (Siah1). Mechanisms to coordinate its glycolytic and stress cascades are likely to be very important for survival and homeostatic control of any living organism. Here we report that apoptosis signal-regulating kinase 1 (ASK1), a representative stress kinase, interacts with both GAPDH and Siah1 and is likely able to phosphorylate Siah1 at specific amino acid residues (T70/T74 and T235/T239). Phosphorylation of Siah1 by ASK1 triggers GAPDH-Siah1 stress signaling and activates a key downstream target, p300 acetyltransferase in the nucleus. This novel mechanism, together with the established S-nitrosylation/oxidation of GAPDH at C150, provides evidence of how the stress signaling involving GAPDH is finely regulated. In addition, the present results imply crosstalk between the ASK1 and GAPDH-Siah1 stress cascades.