Glucose Inhibits Yeast AMPK (Snf1) by Three Independent Mechanisms

Simple Summary Glucose is the preferred carbon source for most cells. Yeast Snf1 (AMPK in mammals) is the main regulator of the response to low glucose availability. In the last years, much progress has been made in understanding the regulation of Snf1. We summarize three different mechanisms that control Snf1 activity: (1) phosphorylation and dephosphorylation of a critical threonine residue; (2) post-translational modification by the addition of a SUMO tag; (3) protonation and de-protonation of a polyhistidine tract. These mechanisms act independently of each other, allowing a flexible response to the availability of carbon sources. Snf1, the fungal homologue of mammalian AMP-dependent kinase (AMPK), is a key protein kinase coordinating the response of cells to a shortage of glucose. In fungi, the response is to activate respiratory gene expression and metabolism. The major regulation of Snf1 activity has been extensively investigated: In the absence of glucose, it becomes activated by phosphorylation of its threonine at position 210. This modification can be erased by phosphatases when glucose is restored. In the past decade, two additional independent mechanisms of Snf1 regulation have been elucidated. In response to glucose (or, surprisingly, also to DNA damage), Snf1 is SUMOylated by Mms21 at lysine 549. This inactivates Snf1 and leads to Snf1 degradation. More recently, glucose-induced proton export has been found to result in Snf1 inhibition via a polyhistidine tract (13 consecutive histidine residues) at the N-terminus of the Snf1 protein. Interestingly, the polyhistidine tract plays also a central role in the response to iron scarcity. This review will present some of the glucose-sensing mechanisms of S. cerevisiae, how they interact, and how their interplay results in Snf1 inhibition by three different, and independent, mechanisms.