SUMOylation regulates the SNF1 protein kinase

Significance The AMP-activated protein kinase (AMPK) of eukaryotes has been called “the cellular fuel gauge” because it is a central regulator of carbon metabolism that senses cellular energy charge. We show that Snf1, the catalytic subunit of AMPK of the yeast Saccharomyces cerevisiae, is modified by attachment of the small ubiquitin-like modifier SUMO, which inhibits Snf1 function. This process provides yet another way cells regulate function of this highly conserved protein kinase. The AMP-activated protein kinase (AMPK) is a major stress sensor of mammalian cells. AMPK’s homolog in the yeast Saccharomyces cerevisiae, the SNF1 protein kinase, is a central regulator of carbon metabolism that inhibits the Snf3/Rgt2-Rgt1 glucose sensing pathway and activates genes involved in respiration. We present evidence that glucose induces modification of the Snf1 catalytic subunt of SNF1 with the small ubiquitin-like modifier protein SUMO, catalyzed by the SUMO (E3) ligase Mms21. Our results suggest that SUMOylation of Snf1 inhibits its function in two ways: by interaction of SUMO attached to lysine 549 with a SUMO-interacting sequence motif located near the active site of Snf1, and by targeting Snf1 for destruction via the Slx5-Slx8 (SUMO-directed) ubiquitin ligase. These findings reveal another way SNF1 function is regulated in response to carbon source.

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