Download Nutrient Sensing through the Plasma Membrane of Eukaryotic Cells

Focused Meeting held at the Royal Agricultural College, Cirencester, 25–29 September 2004. Organized by S. Shirazi-Beechey (Liverpool, U.K.), J. Thevelein
and F. Stolz (Leuven, Belgium). Edited by S. Shirazi-Beechey. Sponsored by Flanders Interuniversity Institute for Biotechnology and Nestlé U.K. Ltd.
Glucose as a hormone: receptor-mediated glucose
sensing in the yeast Saccharomyces cerevisiae
M. Johnston1 and J.-H. Kim
Department of Genetics, Washington University, St. Louis, MO 63110, U.S.A.
Abstract
Because glucose is the principal carbon and energy source for most cells, most organisms have evolved
numerous and sophisticated mechanisms for sensing glucose and responding to it appropriately. This is
especially apparent in the yeast Saccharomyces cerevisiae, where these regulatory mechanisms determine
the distinctive fermentative metabolism of yeast, a lifestyle it shares with many kinds of tumour cells.
Because energy generation by fermentation of glucose is inefficient, yeast cells must vigorously metabolize
glucose. They do this, in part, by carefully regulating the first, rate-limiting step of glucose utilization: its
transport. Yeast cells have learned how to sense the amount of glucose that is available and respond by
expressing the most appropriate of its 17 glucose transporters. They do this through a signal transduction
pathway that begins at the cell surface with the Snf3 and Rgt2 glucose sensors and ends in the nucleus with
the Rgt1 transcription factor that regulates expression of genes encoding glucose transporters. We explain
this glucose signal transduction pathway, and describe how it fits into a highly interconnected regulatory
network of glucose sensing pathways that probably evolved to ensure rapid and sensitive response of the
cell to changing levels of glucose.
Glucose fuels life
Glucose is the principal carbon and energy source for most
cells (perhaps because it is the most abundant monosaccharide
on the earth), and many (all?) organisms have evolved sophisticated means for sensing glucose and utilizing it efficiently.
Microorganisms living in an animal’s gut must be able to
detect the frequent fluctuations in glucose availability they
encounter. Plants must have mechanisms for communicating
between cells in the photosynthetic ‘source’ tissue that produce sugar and cells in ‘sink’ tissues that store sugar. Cancer
cells must realize that their glucose supply is diminishing as
the pace of tumour growth outstrips the capacity for vascularization, and adjust their lifestyle accordingly. The importance
of glucose sensing to mammals is apparent in their remarkable
ability to maintain an almost constant level of glucose in the
bloodstream (approx. 5 mM) both during the brief periods
when they feast and during the long periods when they fast.
Key words: fermentation, glucose, glucose sensing, glucose transport, HXT gene, Saccharomyces
cerevisiae.
Abbreviations used: Hif1, hypoxia-induced transcription factor; YckI, casein kinase I.
1
To whom correspondence should be addressed (email [email protected]).
Nutrient Sensing Biochemical Society Focused Meeting
Nutrient Sensing through the Plasma
Membrane of Eukaryotic Cells
Learning how cells sense and respond to glucose is thus of
great interest and major significance.
Glucose is particularly important to the yeast Saccharomyces cerevisiae. It is by far the preferred carbon source of this
yeast. Yeast cells can sense glucose and utilize it efficiently
over a broad range of concentrations (from a few micromolar to a few molar!). Accordingly, yeasts have evolved
sophisticated mechanisms for sensing the amount of glucose
available and responding appropriately (reviewed in [1,2]).
Yeast’s unusual glucose metabolism
determines its unique lifestyle
S. cerevisiae has an unusual lifestyle: it prefers to ferment
rather than oxidize glucose, even when oxygen is abundant
[3,4]. Glucose is metabolized through glycolysis to pyruvate,
which has two fates (Figure 1). In the presence of oxygen,
most organisms convert pyruvate to carbon dioxide and water
(via the tricarboxylic acid cycle), generating many ATPs (up
to 36 per molecule of glucose used, according to the textbooks, but fewer are actually produced) via oxidative phosphorylation (the thin black arrow in Figure 1). Only when
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Figure 1 Simplified diagram of glucose metabolism in yeast
oxygen becomes limiting do most cells resort to fermentation
(denoted by the thick downwards-pointing arrow in Figure 1), because it yields only 2 ATPs per molecule of glucose
via ‘substrate-level phosphorylation’ of ADP. S. cerevisiae is
one of the few organisms that prefers to ferment glucose,
even when oxygen is abundant. The resulting low yield of
ATP production demands that yeasts aggressively utilize
the available carbon at the expense of their more efficient
competitors [5]. Because this unusual metabolism results in
the production of ethanol and copious amounts of carbon
dioxide, yeasts have been exploited for thousands of years for
food and beverage production [6].
The tendency of most types of cells to resort to fermentation only when oxygen becomes limiting is known as the
‘Pasteur effect’, named after its discoverer [7]. The contrasting lifestyle of yeast cells – their propensity to carry out
aerobic fermentation – is called the ‘Crabtree effect’ after
the oncologist who discovered this phenomenon in mammalian tumour cells in the 1920s [8]. (Essentially the
same phenomenon was discovered independently, also in
tumour cells, and is also called the ‘Warburg effect’ after its
discoverer [9]). In fact, aerobic fermentation has been used
as a diagnostic criterion for tumour cells, and is the basis
of modern tumour imaging techniques, because its demand
for a high rate of glucose uptake renders such cells visible to
the appropriate imaging methods when they are fed radioactive glucose derivatives [10]. The mechanistic basis of the
Crabtree/Warburg effect in tumour cells, though not well
understood, shows some remarkable similarities to the mechanism responsible for this phenomenon in yeasts (more on
this below).
Regulation of gene expression by glucose
enables yeast’s unique lifestyle
Two major factors contribute to yeasts’ propensity to ferment
glucose even when oxygen is abundant. First, the enzyme
catalysing the first step of pyruvate reduction (pyruvate
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decarboxylase) has more capacity than its counterpart that
catalyses the first step of pyruvate oxidation (pyruvate
dehydrogenase) [11]. Secondly, the many enzymes necessary
for glucose oxidation (e.g., electron transport chain proteins
in the mitochondria, tricarboxylic acid cycle enzymes) are
present at low levels in glucose-grown cells because glucose
represses expression of their genes [12]. This is achieved
largely through a signal transduction pathway whose central
component is the Snf1 stress-activated protein kinase,
which catalyses phosphorylation of the Mig1 transcriptional
repressor and thereby regulates its function. The small
amount of ATP obtained from each molecule of glucose that
is fermented requires yeast cells to pump a large amount of
glucose through glycolysis to generate sufficient energy for
life. This is achieved by glucose induction of expression of
many genes encoding proteins necessary for its utilization,
most notably the enzymes of glycolysis [13], and the proteins
that facilitate glucose transport, the first (and rate-limiting)
step in glucose metabolism [14].
Yeast has many glucose transporters
The importance of glucose to yeast is underscored by the large
number of hexose transporters it possesses – 18. At least six
of these (Hxt1, 2, 3, 4, 6 and 7) are known to be glucose transporters [14,15], one (Gal2) is a galactose transporter [16] and
the others (Hxt5 and Hxt8-17) are probably transporters of
other hexoses such as fructose and mannose, which are closely
related to glucose [15]. Each of the glucose transporters has a
different affinity and capacity for glucose [17]. Hxt1 is a lowaffinity, high-capacity transporter that is most useful when
glucose is abundant (>∼1%); Hxt2 is a high-affinity, lowcapacity glucose transporter that is necessary when glucose is
scarce (∼0.2%). The other hexose transporters have evolved
for dealing with different concentrations of glucose and under
different conditions. Thus, yeast cells have many different
glucose transporters to deal with many different conditions.
Several of the glucose transporters are expressed only when
glucose is available, and only under the appropriate conditions [14]. The low-affinity, high-capacity Hxt1 glucose
transporter is only expressed when glucose is abundant; the
high-affinity, low-capacity Hxt2 glucose transporter is only
expressed when glucose is scarce. HXT3, which encodes a
glucose transporter of intermediate affinity, is expressed in
cells exposed to both low (0.2%) and high (2%) levels of
glucose [18].
Mechanism of glucose induction
of HXT gene expression
The signal transduction pathway responsible for induction of
expression of the HXT genes by glucose is shown in Figure 2.
It culminates in the Rgt1 transcription factor, which binds to
the promoters of HXT genes and represses their transcription
in cells grown in the absence of glucose (bottom right in
Figure 2). The Rgt1 repressor does this in conjunction with
Mth1 and Std1, paralogous proteins that bind to Rgt1 and
Nutrient Sensing through the Plasma Membrane of Eukaryotic Cells
Figure 2 Diagram of the Rgt2/Snf3-Rgt1 glucose signal transduction pathway responsible for glucose induction of HXT gene expression
Glucose binding to the Snf3 and Rgt2 glucose sensors activated YckI, which phosphorylates Mth1 and Std1 that are bound to
the C-terminal cytoplasmic tails of the sensors. Phosphorylated Mth1 and Std1 are substrates of the SCFGrr1 ubiquitin-protein
ligase, which targets them for degradation in the proteasome. Rgt1 lacking Mth1 and Std1 can no longer bind to DNA,
resulting in derepression of HXT gene expression.
are required for it to repress transcription. Glucose inhibits
Rgt1 repressor function, leading to derepression of HXT
gene expression. It does this by causing the degradation of
Mth1 and Std1 (middle of Figure 2) [19,20], which robs
Rgt1 of the proteins necessary for its transcriptional repression function, thus leading to derepression of HXT
expression [21,22] (bottom left in Figure 2).
The glucose signal transduction pathway that leads to Mth1
and Std1 degradation begins at the cell surface with two
glucose sensors – Snf3 and Rgt2 – that are probably glucose receptors, since they are clearly related to glucose transporters [23]. The signal generated by the glucose sensors in
response to glucose activates casein kinase I (YckI), a protein
kinase that is tethered to the membrane through a C-terminal
palmitate moiety and that also interacts with the glucose
sensors [20]. Mth1 and Std1 are probably the substrates of
Yck, because they bind to the long C-terminal cytoplasmic
tails of the glucose sensors [24,25]. The proximity of activated
YckI to its substrates causes it to phosphorylate them, which
targets them to the SCFGrr1 ubiquitin-protein ligase. The ensuing ubiquitination of Mth1 and Std1 targets them to the
proteasome for degradation (V. Brachet, unpublished work).
Below are brief summaries of what is known about each component of this glucose sensing and signalling pathway
beginning from the bottom of the pathway.
Rgt1 contains a C6 -Zn2 ‘zinc cluster’ DNA-binding domain that recognizes the sequence 5 CGGANNA3 [22]. It is
unclear how Rgt1 can regulate specific genes through such a
simple sequence. One possibility is that it binds cooperatively
(or synergistically) to multiple sites. Indeed, most of the HXT
genes regulated by Rgt1 have many copies of this sequence
in their upstream regions that operate synergistically, with
multiple sites contributing more than additively to repression.
DNA-binding seems to be the function of Rgt1 that is regulated by glucose: Rgt1 binds to HXT promoters only in
the absence of glucose [22,26]. This is somewhat surprising,
because Rgt1 is known to be a transcriptional activator when
glucose is abundant [27]. How can it do this without binding
to DNA? Rgt1 DNA-binding is regulated by glucose because
Mth1 is required for this function [19,21]: addition of glucose
to cells induces degradation of Mth1, causing Rgt1 to lose its
DNA-binding ability. Mth1 is not directly involved in DNAbinding, because rgt1 mutations that alter its regulation and
cause it to bind to DNA constitutively (even in the presence
of glucose) relieve the requirement of Mth1 for Rgt1 DNA
binding ( J. Polish and J.-H. Kim, unpublished results). Mth1
seems to regulate the ability of Rgt1 to be phosphorylated by
a yet unknown protein kinase [21], which is correlated with
the DNA-binding ability of Rgt1: Rgt1 in glucose-grown
cells is hyperphosphorylated and unable to bind to DNA. It
is surprising that Std1, which is quite similar to Mth1, does
not regulate the DNA-binding activity of Rgt1. Std1 may play
a role in regulating the transcriptional activation function of
Rgt1.
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Degradation of Mth1 (and Std1) is the key event that
enables derepression of HXT gene expression. Mth1 and Std1
are marked for degradation in the proteasome (V. Brachet,
unpublished work) by their ubiquitination, catalysed by the
SCFGrr1 ubiquitin-protein ligase [19]. Proteins must be phosphorylated to be substrates of this enzyme [28], and for
Mth1 and Std1 this is achieved by YckI, encoded by YCK1
and YCK2. This conclusion is supported by the observation
that removing the serine residues in several consensus YckI
phosphorylation sites in Mth1 and Std1 prevents their phosphorylation and subsequent degradation [20]. YckI is located
in the cell membrane because of the palmitate it carries
on its C-terminus [29,30], and it also interacts with the
glucose sensors [20]. This leads to the view that glucose
binding to the glucose sensors induces a change in their conformation that activates the associated YckI, which catalyses phosphorylation of Mth1 and Std1. The C-terminal,
cytoplasmic tails of the glucose sensors enhance signalling,
because they interact with Mth1 and Std1 and thereby bring
them to the vicinity of YckI. Mth1 and Std1 must shuttle
between the nucleus and the cell membrane, because they bind
to Rgt1 in the nucleus and to the glucose sensors at the cell
surface. There is no evidence that the subcellular localization
of Mth1 and Std1 is regulated.
What is the nature of the glucose signal generated by the
glucose sensors, and how does it activate YckI? It seems clear
that signal generation is receptor-mediated, because glucose
metabolism is not necessary for its generation: there are
mutations in the genes encoding the glucose sensors that
cause them to generate a signal even in the absence of glucose
[23,31]. Thus, the glucose signal cannot be a glucose metabolite. The Snf3 and Rgt2 glucose sensors are probably
glucose receptors, because they are clearly derived from glucose transporters and therefore probably have a glucosebinding site [23,32]. The glucose sensors appear to have
lost the ability to transport glucose into the cell [23]. We
believe that binding of glucose to the glucose sensors induces
a conformational change in them that is transmitted to the
associated YckI. In this view, the mutations in the glucose
sensors that cause them constitutively to generate a glucose signal convert the receptors into their glucose-bound
form. To truly understand this signal transduction pathway
we will need to learn how this conformational change in the
glucose sensors activates the protein kinase activity of YckI.
This is a novel signal transduction pathway that employs a
unique type of receptor: a small-molecule transporter that
evolution has hijacked for the purpose of nutrient sensing. Soon after the discovery of the glucose sensors [23], a
similar receptor for amino acids was discovered [33–36]. In
addition, there seems to be another glucose sensing mechanism in S. cerevisiae that employs a G-protein coupled
glucose receptor [37]. We submit that discovery of the glucose
and amino acid sensors has somewhat changed our view
of how cells sense nutrients. The prevailing view was that
this occurs mostly through metabolism of the nutrient, as
is the case for glucose sensing by insulin-producing cells of
the pancreas [38], and is probably the case for the glucose
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repression pathway that operates through the Snf1 protein
kinase and the Mig1 repressor [39]. The discovery of the yeast
glucose and amino acid sensors revealed that these nutrients
can act like hormones to initiate receptor-mediated signalling.
An exciting possibility is that similar nutrient sensors are
operating in mammalian cells [40,41]. A better understanding
of their function in yeast cells is likely to help answer this
important question.
Multiple regulatory mechanisms ensure
appropriate HXT gene expression
Other regulatory mechanisms are superimposed on Rgt1mediated regulation to ensure that the cell expresses only
those glucose transporters best suited for the amount of glucose available. HXT2, which encodes a high-affinity glucose
transporter [42], is induced only by low levels of glucose because its promoter has binding sites for the Mig1
glucose repressor, which represses transcription when glucose
levels are high (Figure 3) [43]. By contrast, expression of
HXT1, which encodes a low-affinity glucose transporter [42],
is induced only by high levels of glucose because of regulation by another mechanism (whose components have not
yet been identified) that requires high levels of glucose [43].
In addition, HXT1 expression is induced by high osmolarity
through the HOG signal transduction pathway that culminates in the Sko1 transcription factor [44]. It seems likely that
contributions of other regulatory mechanisms to regulation
of HXT gene expression will be discovered.
Furthermore, feedback and feedforward regulatory loops
govern the expression of genes involved in the Snf3/Rgt2
glucose sensing pathway. We can recognize three such controls (shown in Figure 3) [45]. (1) The glucose induction
pathway regulates itself through Rgt1-mediated glucose
induction of STD1 expression. This is feedback regulation:
glucose inhibits Std1 function by stimulating its degradation
while at the same time inducing STD1 expression through the
Snf3/Rgt2-Rgt1 signalling pathway. Thus, STD1 expression
is turned up at the same time that Std1 levels are decreasing
in response to glucose. This regulation should serve to
dampen glucose induction of gene expression. It should also
provide for rapid reestablishment of repression. (2) Glucose
repression regulates the glucose induction pathway through
Mig1- (and Mig2-) mediated repression of MTH1 and
SNF3 expression. This regulation of MTH1 expression constitutes feedforward regulation: glucose reduces MTH1 expression at the same time that it stimulates proteasomemediated degradation of Mth1. This regulation reinforces the
inhibitory effect of glucose on Mth1 function and should
ensure maximal glucose induction of Rgt1-repressed genes.
Repression of SNF3 expression by high levels of glucose
probably reflects the likely function of Snf3 as a high-affinity
glucose sensor (a sensor of low levels of glucose). (3) The
Mig2 repressor is activated by glucose because of induction
of expression of MIG2 via the Snf3/Rgt2-Rgt1 glucose induction pathway. Thus, the Snf3/Rgt2-Rgt1 pathway, which
we formerly thought was responsible only for induction
Nutrient Sensing through the Plasma Membrane of Eukaryotic Cells
Figure 3 The glucose induction and glucose repression pathways cross-regulate each other
The left half of this Figure shows the Rgt2/Snf3-Rgt1 glucose induction pathway; the right half is a diagram of the Snf1-Mig1
glucose repression pathway. Lines with bars denote transcriptional repression; lines with arrows denote transcriptional
activation. The numbers refer to feedback and feedforward regulation described in the text.
of gene expression, also contributes to glucose repression of
gene expression, because one of the outputs of the glucose
signal that is generated by the Rgt2 and Snf3 glucose sensors
is glucose repression of expression of genes that are targets of
Mig2.
pressor gene. These similarities in the two cell types bolster
our confidence that a deeper understanding of the mechanisms responsible for glucose induction of gene expression in
yeasts will inform cancer biology, and may even suggest opportunities for developing therapeutic interventions.
Similarities in the basis of aerobic
fermentation in yeast and tumour cells
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Received 21 September 2004