Sir2 plays a key role in cell fate determination upon SAPK activation

Abstract

Although the benefit of sirtuin activation in age-related diseases is well-characterized, the benefit of sirtuin activation in acute diseases has been elusive. Here we discuss that, at least in yeast, Sir2 activation prevents programmed cell death induced by the sustained activation of the stress activated protein kinase (SAPK) Hog1, the yeast homologue of the p38 SAPK. Sir2 prevents ROS formation and maximize cell survival upon SAPK activation. The conserved function of Sir2 in age-related diseases and the conserved role of SAPKs open the possibility of a novel role for sirtuins in cell fate determination in eukaryotic cells.

Figure 1

Tentative model that depicts the effect of Hog1 and sirtuins in dictating cell-fate determination. Hog1 inhibits mitochondrial respiration, which results in an increase in reactive oxygen species (ROS) accumulation that leads to cell death. In parallel, Hog1 induces PNC1 expression. Pnc1 activates Sir2, which mediates a decrease in ROS accumulation. Sir2 activation by the stress-activated protein kinase Hog1 relieves the Hog1-induced oxidative stress to prevent apoptotic cell death.

Figure 2

Scheme of Hog1-induced Msn2/Msn4 dependent gene expression upon SCF^cdc4 regulation. Activation of Hog1 SAPK induces the activation of Msn2/Msn4-dependent genes, such as PNC1. The E3 _SCFcdc4 ubiquitin ligase ubiquitylates the transcription factors to promote their degradation. Partial inactivation of SCF^cdc4 decreases Msn2/4 degradation, which results in an increased accumulation of the TFs at the promoters and to an increase in Msn2/Msn4 dependent gene expression.