Abstract
The SNF1 kinase in Saccharomyces cerevisiae is an excellent model to study the regulation and function of the AMP-dependent protein kinase (AMPK) family of serine-threonine protein kinases. Yeast discoveries regarding the regulation of this non-hormonal sensor of metabolic/environmental stress are conserved in higher eukaryotes, including poly-ubiquitination of the α-subunit of yeast (Snf1) and human (AMPKα) that ultimately effects subunit stability and enzyme activity. The ubiquitin-cascade enzymes responsible for targeting Snf1 remain unknown, leading us to screen for those that impact SNF1 kinase function. We identified the E2, Ubc1, as a regulator of SNF1 kinase function. The decreased Snf1 abundance found upon deletion of Ubc1 is not due to increased degradation, but instead is partly due to impaired SNF1 gene expression, arising from diminished abundance of the Forkhead 1/2 proteins, previously shown to contribute to SNF1 transcription. Ultimately, we report that the Fkh1/2 cognate transcription factor, Hcm1, fails to enter the nucleus in the absence of Ubc1. This implies that Ubc1 acts indirectly through transcriptional effects to modulate SNF1 kinase activity.
Highlights
The SNF1 kinase class of serine/threonine kinases, which includes the AMP-dependent protein kinase (AMPK) in other systems, are of widespread interest because of their important roles in glucose homeostasis, stress resistance, and aging [1,2,3]
The SNF1 kinase in Saccharomyces cerevisiae is an excellent model to study the regulation and function of the AMP-dependent protein kinase (AMPK) family of serine-threonine protein kinases
The SNF1 kinase is strongly evolutionarily conserved from yeast to humans, and fundamental mechanisms regulating SNF1 kinase activity in yeast have been proven to be likewise used in higher eukaryotes, including the essential phosphorylation on its α subunit, regulated dephosphorylation, allosteric subunit associations, and nuclear shuttling [12]
Summary
The SNF1 kinase class of serine/threonine kinases, which includes the AMP-dependent protein kinase (AMPK) in other systems, are of widespread interest because of their important roles in glucose homeostasis, stress resistance, and aging [1,2,3]. These enzymes are inactive under optimal conditions, yet are rapidly activated in response to a wide variety of nutritional and stress cues. SNF1 kinase directly phosphorylates a variety of downstream targets, including the nuclear target Mig1 [7] and the cytosolic target Rod1 [8]. Ubiquitin (Ub) becomes covalently attached to target proteins through the sequential action of Ub activating (E1), conjugating (E2), and ligase (E3) activities: in yeast there is a single E1, a finite well-described group of eleven E2s, and an ever-expanding recognition of E3 ligase activities
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