Signalling 2011: a Biochemical Society Centenary Celebration
Growth and metabolic control of lipid signalling
at the Golgi
Hailan Piao and Peter Mayinger1
Division of Nephrology and Hypertension, and Department of Cell and Developmental Biology, Oregon Health and Science University, 3181 Sam Jackson Park
Road, Portland, OR 97239, U.S.A.
Abstract
PtdIns4P is a key regulator of the secretory pathway and plays an essential role in trafficking from the Golgi.
Our recent work demonstrated that spatial control of PtdIns4P at the ER (endoplasmic reticulum) and
Golgi co-ordinates secretion with cell growth. The central elements of this regulation are specific
phosphoinositide 4-kinases and the phosphoinositide phosphatase Sac1. Growth-dependent translocation
of Sac1 between the ER and Golgi modulates the levels of PtdIns4P and anterograde traffic at the Golgi.
In yeast, this mechanism is largely dependent on the availability of glucose, but our recent results in
mammalian cells suggest that Sac1 phosphatases play evolutionarily conserved roles in the growth control
of secretion. Sac1 lipid phosphatase plays also an essential role in the spatial control of PtdIns4P at the Golgi
complex. A restricted pool of PtdIns4P at the TGN (trans-Golgi network) is required for Golgi integrity and for
proper lipid and protein sorting. In mammalian cells, the stress-activated MAPK (mitogen-activated protein
kinase) p38 appears to play a critical role in transmitting nutrient signals to the phosphoinositide signalling
machinery at the ER and Golgi. These results suggest that temporal and spatial integration of metabolic and
lipid signalling networks at the Golgi is required for controlling the secretory pathway.
Introduction
Stimulation of cell growth in eukaryotes requires both
increased biosynthetic capacity and enhanced membranebased transport of macromolecules. It is well established
that ribosome biogenesis and protein translation are rapidly
up-regulated upon growth stimulation, and regulatory
mechanisms have been characterized [1]. Analysis of yeast
mutants showed that a functional secretory pathway is also
critical for cell-surface growth [2]. Yet how anterograde
trafficking of proteins and lipids is controlled by growth and
nutrient-based signals is largely unknown. The importance
of secretion for cell growth has been highlighted in several
studies, suggesting that growth of cancer cells requires
stimulated membrane traffic. For example, expression of a
subset of trafficking regulators belonging to the family of
Rab and Arf GTPases are up-regulated in liver, breast and
ovarian cancer [3,4]. Among the different classes of membrane
transport regulators, phosphoinositide lipids play a particularly prominent role. The different phosphoinsositide species
display unique compartment-specific distributions within
the cell and provide spatial cues for membrane trafficking
[5]. Within the secretory pathway, PtdIns4P appears to
be the key phosphoinositide regulator [6]. PtdIns4P is
concentrated at Golgi membranes and has essential functions
in Golgi integrity, regulation of Golgi enzyme localization
Key words: Golgi, lipid signalling, phosphoinositide, Sac1, secretory pathway.
Abbreviations used: COPI, coat protein complex I; COPII, coat protein complex II; Dol-P-Man,
dolichol phosphate mannose; ER, endoplasmic reticulum; GOLPH3, Golgi phosphoprotein 3; MAPK,
mitogen-activated protein kinase; MKK, MAPK kinase; NCS1, neuronal calcium sensor 1; Osh,
oxysterol-binding homology; PI4K, phosphoinositide 4-kinase; PKD, protein kinase D; TGN, transGolgi network.
1
To whom correspondence should be addressed (email [email protected]).
Biochem. Soc. Trans. (2012) 40, 205–209; doi:10.1042/BST20110637
and anterograde trafficking from the Golgi [6]. The present
review summarizes our current understanding of how Golgi
PtdIns4P levels are regulated by metabolic and growth
signals. The central elements of this control mechanisms
are evolutionarily conserved and consist of specific lipid
signalling enzymes that associate with the Golgi under certain
growth conditions. This growth-specific regulation of Golgi
PtdIns4P is crucial for co-ordinating the capacity of the
secretory pathway with cell proliferation.
Metabolic control of Golgi
phosphoinsoitides in yeast
A genetic screen in yeast for novel regulators of secretion
discovered a critical role for Golgi PtdIns4P in controlling
anterograde trafficking from the Golgi to the plasma
membrane [7]. Yeast cells have three PI4Ks (phosphoinositide
4-kinases), namely Pik1p, Stt4p and Lsb6p [8–10]. Both Stt4p
and Pik1p are essential for cell viability, but regulate different
cellular processes [11–13]. Pik1p localizes at the Golgi and
is essential for anterograde trafficking [7]. In contrast, Stt4p
resides at the plasma membrane and synthesizes a pool of
PtdIns4P that is converted into PtdIns(4,5)P2 and plays a
role in actin cytoskeletal organization and protein kinase
C signalling [12]. Both Pik1p and Stt4p play also distinct
roles in regulating MAPK (mitogen-activated protein kinase)
signalling [14,15].
The most important lipid phosphatase that controls
intracellular levels of PtdIns4P is the polyphosphoinositide
phosphatase Sac1p [16]. The yeast SAC1 gene was originally
identified in a screen for suppressors of actin mutations,
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Biochemical Society Transactions (2012) Volume 40, part 1
but the functional basis for this genetic interaction remains
unclear [17]. A conserved N-terminal lipid phosphatase
domain in yeast Sac1p (also termed the Sac domain) is the
defining property of a specific class of lipid phosphatases
[18]. Sac phosphatase domain-containing proteins are able
to dephosphorylate a variety of phosphoinositide species
including PtdIns3P, PtdIns4P and PtdIns(3,5)P2 [18]. The
recently resolved crystal structure of the Sac phosphatase
domain of yeast Sac1p shows that the Sac domain comprises
two closely packed subdomains, a unique N-terminal domain
and a catalytic lipid phosphatase subdomain, which contains
a conserved catalytic CX5 R(T/S) motif [18,19]. Topology
analysis showed that Sac1p is a type II membrane protein
containing two transmembrane domains near the C-terminus
[20]. Among the Sac domain-containing lipid phophatases,
Sac1p is the only integral membrane protein, and the majority
of Sac1p localizes at the Golgi complex and at the ER
(endoplasmic reticulum) [20,21]. Deletion of yeast SAC1
results in a dramatic elevation of cellular PtdIns4P levels and
leads to an increase in the forward transport of Chs3p chitin
synthase from its intracellular stores to the cell periphery and
thus leads to specific cell wall defects [22,23]. Elimination of
yeast Sac1p additionally causes impaired ATP transport into
the ER [24].
In contrast with its mammalian orthologues, yeast Sac1p
lacks any consensus sequence motifs that regulate retrieval to
the ER [25]. Previous studies have shown that Dol-P-Man
(dolichol phosphate mannose) synthase Dpm1p interacts
with Sac1p and is responsible for ER localization of Sac1p
during exponential cell growth [25] (Figure 1). Dpm1p
synthesizes Dol-P-Man, which is an essential mannosyl
donor for luminal steps in oligosaccharide biosynthesis at
the ER [26]. The interaction between Sac1p and Dpm1p
persists only during exponential growth and is rapidly
abolished when cell growth slows due to restricted nutrient
availability [25]. Under glucose-starved conditions, Sac1p
quickly translocates to the Golgi, which requires the adaptor
protein Rer1p and the COPII (coat protein complex II)
[25,27] (Figure 1). The glucose-starvation-induced ER–Golgi
shuttling of Sac1p is promptly reversed when glucose is added
back [25] (Figure 1). Golgi association of the PI4K Pik1 is also
regulated by glucose. Under high glucose conditions, Pik1p
localizes at the Golgi by binding to its non-catalytic subunit
Frq1p and produces a Golgi-specific pool of PtdIns4P [27,28]
(Figure 1). During nutrient deprivation, the Pik1p–Frq1
complex is rapidly released from the Golgi to the cytoplasm
[27,28] (Figure 1). A portion of Pik1 also translocates into
the nucleus [28] (Figure 1). This reaction is rapidly reversed
upon restoration of nutrient supply [27,28].
Nutrient-dependent Sac1p localization controls distinct
pools of PtdIns4P, generated by different lipid kinases
[27,29,30]. When nutrients are plentiful, Sac1p resides at
the ER, but controls a specific pool of PtdIns4P at the
plasma membrane synthesized by Stt4p lipid kinase [29,30].
This reaction occurs at ER–plasma membrane contact sites
and requires the small ER adaptor proteins Scs2p/Scs22p and
Osh (oxysterol-binding homology) proteins that act as
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Authors Journal compilation Figure 1 Glucose regulation of Golgi phosphoinositides in yeast
When nutrients are not limiting, yeast cells grow exponentially and
Sac1p localizes to the ER in a complex with Dpm1p. Under these
conditions, Sac1p is activated by Osh3p and turns over PtdIns4P that is
synthesized by Stt4 at the plasma membrane at ER–plasma membrane
(PM) contact sites. Simultaneously, the Pik1p–Frq1p lipid kinase
complex generates a Golgi-specific PtdIns4P pool, which stimulates
secretion. Glucose starvation triggers translocation of Sac1p to the
Golgi, where it down-regulates PtdIns4P. Anterograde transport of Sac1p
requires COPII vesicular traffic and the adaptor Rer1p. Starvation also
prompts rapid release of Pik1p–Frq1p from Golgi membranes into the
cytoplasm and also induces translocation of Pik1p into the nucleus. PI,
phosphatidylinositol; PI(4)P, PtdIns4P.
PtdIns4P sensors and activate Sac1 phosphatase activity [30]
(Figure 1). The physiological significance of this interesting
enzymatic reaction is unclear, but, given that individual yeast
Osh proteins associate with different intracellular membranes
[31], this type of regulation may represent a general
mechanism for controlling phosphoinositide signalling at
organellar membrane interfaces. During glucose starvation,
Sac1p quickly translocates to the Golgi and turns over a
pool of PtdIns4P that is generated by Pik1p, which in turn
down-regulates anterograde traffic [25]. Glucose availability
therefore regulates the Golgi association of Sac1p lipid
phosphatase and the Pik1p–Frq1p lipid kinase complex in
an opposite manner and thus aligns the trafficking capacity
of the Golgi with cell growth conditions.
Phosphoinositide signalling at the Golgi
and growth control of secretion in
mammalian cells
The mechanism for regulating Golgi PtdIns4P is evolutionarily conserved and present in organisms from yeast to
Signalling 2011: a Biochemical Society Centenary Celebration
Figure 2 Mitogen-dependent regulation of Golgi
phosphoinositides in mammals
In serum-starved cells, Sac1 oligomerizes and translocates to the Golgi
via COPII vesicular traffic, which in turn down-regulates Golgi PtdIns4P
and constitutive secretion. After growth factor stimulation, p38 MAPK
activity is required for dissociation of SAC1 complexes, which triggers
retrograde traffic and redistribution of Sac1 to the ER. Activation of
PI4KIIIβ by PKD induces biosynthesis of Golgi PtdIns4P. PI4KIIα also
generates Golgi PtdIns4P, but it is unclear whether this enzyme is
regulated by growth signals. PI, phosphatidylinositol; PI(4)P, PtdIns4P.
mammals. As in yeast, the mammalian Sac1 lipid phosphatase
orthologues appear to be central elements in this regulation
[16]. However, Golgi PtdIns4P in mammals is synthesized
by several PI4Ks [32]. Previous studies have shown that
both PI4KIIα and PI4KIIIβ are involved in generating
PtdIns4P at the Golgi [33,34]. These kinases may control
functionally distinct Golgi PtdIns4P pools and perhaps
regulate different lipid and protein trafficking pathways [34–
37]. PI4KIIIβ is the closest homologue of yeast Pik1p and
forms a complex with the N-myristoylated Ca2 + -binding
NCS1 (neuronal calcium sensor 1), which is homologous
with yeast Frq1p [38]. Whether the PI4KIIIβ–NCS1 complex
dissociates from the Golgi upon serum or nutrient starvation
remains unknown, but the activity of PI4KIIIβ was shown to
be regulated by PKD (protein kinase D) and 14-3-3 proteins
[39].
Like yeast Sac1p, mammalian Sac1 proteins translocate
between the ER and Golgi in response to growth conditions,
which is regulated by growth factors rather than glucose
[40] (Figure 2). Serum starvation induces almost quantitative
accumulation of Sac1 at the Golgi [40]. This trafficking
reaction is functionally equivalent to the glucose starvationinduced Golgi accumulation of Sac1p in yeast and also
results in specific down-regulation of Golgi PtdIns4P, which
dampens anterograde traffic [40]. Differently from yeast
Sac1p, all mammalian Sac1 orthologues contain a canonical
dilysine COPI (coat protein complex I) recognition motif
[41]. Consequently, trafficking of mammalian Sac1 proteins is
regulated differently from yeast Sac1p. Under normal growth
conditions, the dilysine motif is sufficient for continuous
retrieval of Sac1 from the Golgi to the ER, where the
majority of the enzyme is localized in steady state [40,41].
Starvation-induced accumulation of mammalian Sac1 at
the Golgi requires oligomerization of the protein, which
depends on a leucine repeat motif present at the N-terminal
cytoplasmic domain [40,41]. The exact mechanism by which
oligomerization facilitates anterograde trafficking of Sac1
is unclear, but it is possible that active recruitment into
COPII vesicles plays a role. Previous studies have shown
that oligomerization of membrane cargos such as plasma
membrane receptors can be a requirement for ER exit
[42]. Alternatively, oligomerization could mask the COPIinteracting motif, which would disable retrograde trafficking
of Sac1.
The shift in localization of Sac1 from the ER to the Golgi
occurs within 24–48 h of serum starvation [40]. It therefore
appears likely that the actual ER–Golgi redistribution of Sac1
is initiated after cells have exited the cell cycle. In contrast,
when quiescent cells are stimulated by growth factors, Sac1
rapidly returns to the ER with a half-time of approximately
15 min, and this reaction appears to be one of the earliest
events triggered by growth signalling [40] (Figure 2). The
growth-factor-induced stimulation of retrograde trafficking
of Sac1 coincides with the dissociation of Sac1 oligomers and
requires p38 MAPK activity [40] (Figure 2). Whether Sac1
itself is a p38 MAPK target is unknown. It is clear, however,
that activation of p38 MAPK by expression of activated
alleles of the upstream MKK (MAPK kinase) 3 or MKK6
kinases is sufficient to trigger Sac1 oligomer dissociation and
stimulate retrograde traffic, even in the absence of growth
factor signalling [40]. These results indicate that trafficking
of Sac1 is regulated not only during proliferation and during
quiescence, but also probably when cells are exposed to
stressors that activate p38 MAPK. Interestingly, inhibition
of p38 MAPK by specific drugs eliminates the rapid upregulation of secretion that is normally observed when
cells are stimulated with growth factors [40]. These results
provide direct evidence that both p38 MAPK signalling
and Sac1 lipid phosphatase activity play central roles in
regulating constitutive secretion in response to starvation and
proliferation signals.
Role for Sac1 lipid phosphatase in spatial
regulation of Golgi PtdIns4P
Mammalian Sac1 has an additional important housekeeping
function at the Golgi during cell proliferation that is necessary
for the spatial regulation of PtdIns4P. In rapidly dividing
cells, the majority of Sac1 resides at the ER [40,41]. Yet a
certain proportion of Sac1 is also located at the Golgi, even
when cells are stimulated with growth factors [40,43]. The
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Golgi-resident portion of SAC1 is restricted to cisternal Golgi
regions and absent from the TGN (trans-Golgi network) [43].
This distribution of Sac1 results in a steep cis–trans PtdIns4P
gradient, with the majority of PtdIns4P remaining confined
to the TGN. The spatial segregation of PtdIns4P and Sac1
is dependent on Sac1 phosphatase activity [43]. These results
therefore provide a mechanistic explanation for the polarized
pools of Golgi PtdIns4P reported previously [44].
What is the physiological significance of spatially restricted
Golgi PtdIns4P pools? Many of the effectors of Golgi
PtdIns4P also bind to activated ARF1 (ADP-ribosylation
factor 1) and play a role in anterograde trafficking from
the TGN [32]. The concentrated pool of PtdIns4P at the
TGN provides directionality for these processes. Golgi
PtdIns4P is also important for the targeting of several lipidtransfer proteins [32]. In addition, PtdIns4P is required
for the regulation of the Golgi phospholipid flippase Drs2
[45]. These factors appear to play a role in controlling
the lipid composition at the TGN, which may facilitate
formation of vesicular and tubular transport carriers [32].
This idea is supported by the fact that the PtdIns4P effector
FAPP2 (four-phosphate adaptor protein 2) not only functions
as a glucosylceramide-transfer protein, but also has an
independent activity in membrane tubule formation [37,46–
48]. Finally, PtdIns4P interacts with proteins that play a role
in Golgi morphology. For example the PtdIns4P effector
GOLPH3 (Golgi phosphoprotein 3) binds to unconventional
myosins and seems to participate in shaping the Golgi [49].
Vps74 (vacuolar protein sorting 74), the yeast homologue of
GOLPH3, also binds to PtdIns4P, but, in addition, interacts
with several Golgi glycosylation enzymes and regulates
the proper Golgi localization of these proteins [50]. A
role for spatially controlled Golgi PtdIns4P pools in Golgi
morphology and retrograde trafficking of glycosylation
enzymes is supported by Sac1 siRNA (small interfering
RNA) knockdown experiments. Elimination of Sac1 lipid
phosphatase induces delocalization of Golgi PtdIns4P and
causes plasma membrane accumulation of glycosylation
enzymes [43]. In addition, Golgi morphology and mitotic
spindle organization is significantly impaired [51]. PtdIns4P
therefore plays multiple spatially defined roles at the Golgi.
Additional regulatory factors, such as small GTPases from the
Arf and Rab family, are required in a coincidence detection
mechanism to selectively recruit effector proteins to the
appropriate sites.
Conclusions
Among the seven described phosphoinositide lipids,
PtdIns4P is the most important regulator of the secretory
pathway. PtdIns4P plays critical roles in regulating Golgi
morphology and stability, but is particularly important for
facilitating lipid and protein sorting at the Golgi. Metabolic
and mitogenic control of PtdIns4P links the capacity of the
secretory pathway to cell growth and proliferation. Although
lipid phosphatases and kinases that regulate Golgi PtdIns4P
levels have been identified, it remains unresolved how growth
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Authors Journal compilation and nutrient signals are transmitted to the lipid signalling
machinery at the ER and Golgi. Further characterization of
the control of Golgi phosphoinositides will be important
to gain new insights into the cross-talk between growth
signalling and the secretory pathway, which may help to
identify novel drug targets against the uncontrolled cell
growth in cancer and other cell proliferative diseases.
Funding
This work was supported in part by the National Institutes of Health
[grant numbers GM71569 and GM84088].
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Received 21 June 2011
doi:10.1042/BST20110637
C The
C 2012 Biochemical Society
Authors Journal compilation 209