Metabolic signals trigger glucose-induced inactivation of maltose permeasein Saccharomyces

Organisms such as Saccharomyces capable of utilizing several different suga rs selectively ferment glucose when less desirable carbon sources are also available. This is achieved by several mechanisms. Glucose downregulates th e transcription of genes involved in utilization of these alternate carbon sources, Additionally, it causes posttranslational modifications of enzymes and transporters, leading to their inactivation and/or degradation. Two gl ucose sensing and signaling pathways stimulate glucose-induced inactivation of maltose permease, Pathway 1 uses Rgt2p as a sensor of extracellular glu cose and causes degradation of maltose permease protein. Pathway 2 is depen dent on glucose transport and stimulates degradation of permease protein an d very rapid inactivation of maltose transport activity, more rapid than ca n be explained by loss of protein alone. In this report, we characterize si gnal generation through pathway 2 using the rapid inactivation of maltose t ransport activity as an assay of signaling activity. We find that pathway 2 is dependent on HXK2 and to a lesser extent HXK1. The correlation between pathway 2 signaling and glucose repression suggests that these pathways sha re common upstream components. We demonstrate that glucose transport via ga lactose permease is able to stimulate pathway 2. Moreover, rapid transport and fermentation of a number of fermentable sugars (including galactose and maltose, not just glucose) are sufficient to generate a pathway 2 signal. These results indicate that pathway 2 responds to a high rate of sugar ferm entation and monitors an intracellular metabolic signal. Production of this signal is not specific to glucose, glucose catabolism, glucose transport b y the Hxt transporters, or glucose phosphorylation by hexokinase 1 or 2. Si milarities between this yeast glucose sensing pathway and glucose sensing m echanisms in mammalian cells are discussed.