Conventional and emerging roles of the energy sensor Snf1/AMPK in Saccharomyces cerevisiae

Abstract

All proliferating cells need to match metabolism, growth and cell cycle progression with nutrient availability to guarantee cell viability in spite of a changing environment. In yeast, a signaling pathway centered on the effector kinase Snf1 is required to adapt to nutrient limitation and to utilize alternative carbon sources, such as sucrose and ethanol. Snf1 shares evolutionary conserved functions with the AMP-activated Kinase (AMPK) in higher eukaryotes which, activated by energy depletion, stimulates catabolic processes and, at the same time, inhibits anabolism. Although the yeast Snf1 is best known for its role in responding to a number of stress factors, in addition to glucose limitation, new unconventional roles of Snf1 have recently emerged, even in glucose repressing and unstressed conditions. Here, we review and integrate available data on conventional and non-conventional functions of Snf1 to better understand the complexity of cellular physiology which controls energy homeostasis.

Keywords: DNA damage; aging; budding yeast; cell cycle; endocytosis; glucose repression; metabolism; signaling; stress response; transcription.

Figure 1. FIGURE 1: Schematization of the activation of Snf1 and its main conventional functions.

Snf1 complex is composed by the α subunit Snf1, the γ subunit Snf4 and one of three alternative β subunits Gal83, Sip1 or Sip2. Snf1 is phosphorylated on T210 by the upstream kinases Sak1, Tos3 and Elm1, while it is de-phosphorylated by the phosphatase complex Glc7/Reg1. When active, Snf1 phosphorylates transcription factors which regulate the expression of genes involved in glucose transport, stress response and glucose repression. In addition, Snf1 directly phosphorylates some metabolic enzymes. See text for details.

Figure 2. FIGURE 2: Network of Snf1 physical interactors.

The network reports the known physical associations obtained from SGD (Saccharomyces Genome Database, http://www.yeastgenome.org. Interactors are clustered according to their function and colored differently. When the interactor is also a substrate of Snf1 according to the Yeast Kinase Interaction Database (KID, http://www.moseslab.csb.utoronto.ca/KID; 44), the edge is colored in red if phosphorylation was analyzed by low throughput assays (LTP in vitro kinase assays; in vitro phosphorylation site mapping; in vivo phosphorylation site mapping; phosphorylation reduced or absent in kinase mutant) or in blue if phosphorylation was assayed only by high throughput analysis (protein chip data for in vitro phosphorylated substrate; HTP in vitro phosphorylation). Data visualization and analysis was performed with Cytoscape .

Figure 3. FIGURE 3: A model of the regulatory role of Snf1 during the cell cycle.

At the G1/S phase transition, Snf1 promotes the binding of Swi4, Mbp1 and Swi6 proteins to G1 promoters and favors the proper recruitment of the RNA Polymerase II. From bud emergence, active Snf1 is localized to the bud neck, in a septin-dependent manner. At the metaphase-to-anaphase transition, Snf1, as part of the Kar9-dependent pathway, promotes spindle alignment along the mother-bud axis and guarantees proper nuclei segregation during mitosis. See text for details.