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Prepublished online as a Blood First Edition Paper on June 21, 2002; DOI 10.1182/blood-2002-04-1149.
 Previous Article | Table of Contents | Next Article 
Blood, 15 October 2002, Vol. 100, No. 8, pp. 2692-2695
REVIEW ARTICLE
Current molecular models for NADPH oxidase regulation by Rac
GTPase
Gary M. Bokoch and
Becky A. Diebold
From the Departments of Immunology and Cell Biology,
The Scripps Research Institute, La Jolla, CA.
 |
Abstract |
Reactive oxygen species (ROS) have been increasingly recognized as
important components of cell signaling in addition to their well-established roles in host defense. The formation of ROS in phagocytic and nonphagocytic cells involves membrane-localized and Rac
guanosine triphosphatase (GTPase)-regulated reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase(s). We discuss here the
current molecular models for Rac GTPase action in the control
of the phagocytic leukocyte NADPH oxidase. As a mechanistically detailed example of Rac GTPase signaling, the NADPH oxidase provides a
potential paradigm for signaling by Rho family GTPases in general.
(Blood. 2002;100:2692-2695)
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Introduction |
Phagocytic leukocytes play major roles in the innate immune response to
pathogens. An important component of this response is the ability of
leukocytes to generate reactive oxygen species (ROS) via a
membrane-associated reduced nicotinamide adenine dinucleotide phosphate
(NADPH) oxidase.1,2 This multicomponent enzyme utilizes
electrons derived from intracellular NADPH to generate superoxide
anion, which subsequently dismutes to H2O2 and
results in the formation of other ROS that are used for host defense. However, the inappropriate or excessive action of this system results
in inflammatory disorders. The NADPH oxidase was the first identified
and remains one of the best-characterized Rho guanosine triphosphatase (GTPase)-regulated systems. It has been shown
that either Rac1 or Rac2 GTPase is required for oxidase activity in cell-free systems,3,4 with Rac2 being the predominantly
active isoform in human neutrophils.5 Additional evidence
has established that Rac2 is an integral and required component of the
NADPH oxidase in the intact leukocyte, including the demonstration that
rac2 / neutrophils had significantly reduced
or absent superoxide production in response to various
stimuli.6-8
Recently, homologs of the cytochrome b component
gp91phox (see "Components and regulation of
the phagocyte NADPH oxidase") of the phagocyte NADPH
oxidase, termed Nox, have been found in several tissues (reviewed by Lambeth9). These new NADPH
oxidases produce low levels of oxidants that appear to be used
as signals for a variety of cellular activities, including cell growth
and transformation. It has been known for some time that Ras and Rac
GTPases regulate signaling pathways that are critical for mitogenesis
and oncogenesis. Transient expression of a constitutively activated
form of Ras in NIH3T3 cells induced a significant increase in
intracellular ROS that was inhibitable by expression of a dominant
negative allele of either Ras or Rac1.10,11 ROS production
was suppressed by treatment with diphenylene iodonium (DPI), an
inhibitor of the phagocyte NADPH oxidase, suggesting that a Nox protein
may be involved. Rac1 also regulates ROS production leading to
reperfusion injury during reoxygenation of vascular smooth
muscle.12,13 Recombinant adenoviral expression of a
dominant negative Rac1 suppressed tissue damage in an in vivo model of
mouse hepatic ischemia/reperfusion injury. This was also observed in
mice deficient for the gp91phox of phagocytic NADPH
oxidase, suggesting that the Rac mutant inhibited ROS production by a
Nox system rather than by one employing
gp91phox.13 Thus, it appears that ROS
production in nonphagocytic cells may involve the regulation of an
NADPH oxidase-like enzyme by Rac GTPase. Understanding how this system
is regulated in phagocytic leukocytes is therefore likely to have
important implications for understanding the regulation of ROS
formation in nonphagocytic cells as well. We discuss here current
models for the action of the Rac GTPase in phagocyte NADPH oxidase function.
| |
Components and regulation of the phagocyte NADPH oxidase |
The NADPH oxidase system of neutrophils and other phagocytic
leukocytes is composed of multiple membrane-associated (cytochrome b558) and cytosolic components (Rac,
p67phox, p47phox,
p40phox [Figure
1]). The active, fully assembled oxidase catalyzes the one electron
reduction of oxygen to produce superoxide anion using NADPH as
substrate. When the leukocyte is activated through the action of
inflammatory mediators (soluble chemoattractants, chemokines, or
phagocytic particles), the cytosolic oxidase component
p47phox becomes phosphorylated on multiple sites
through the action of several kinases. The phosphorylation of
p47phox is thought to lead to the disruption of
an inhibitory intramolecular interaction that exposes SH3 domains in
p47phox for binding to proline-rich regions of
other NADPH oxidase components (reviewed by Babior,1
Lambeth,2 and DeLeo and Quinn14). Cytosolic
p47phox exists both in a free form and in
complexes with the cytosolic oxidase components,
p67phox and p40phox. The
phosphorylation-induced conformational change(s) in
p47phox results in translocation of a
p47phox/p67phox complex
to the membrane, where it interacts via multiple binding sites with the
integral membrane protein, flavocytochrome b558 (cytochrome
b [cyt b]) to form an active enzyme complex.2,14 The active oxidase also requires the translocation of Rac GTPase (see
below), which occurs simultaneously, but dissociably, from the
translocation of the
p47phox/p67phox
complex.5,15 Cyt b possesses 2 subunits,
gp91phox and p22phox, with the
larger subunit containing an NADPH binding site, 2 heme groups, and
bound flavin adenine dinucleotide (FAD).2 The
formation of this minimal protein complex allows electrons to flow via
a 2-step mechanism from NADPH to FAD (step 1) and then from FAD to the
heme of cyt b and finally to molecular oxygen (step 2), whose reduction
leads to the formation of superoxide anion. The cytosolic component
p40phox 16 may play a role in regulating the
response of the system to phosphatidylinositol-3-phosphate in
vivo17 but is not required for NADPH oxidase activity in
the cell-free system.
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| Figure 1.
Activation and assembly of the
phagocyte NADPH oxidase.
Upon stimulation of human neutrophils by inflammatory mediators,
membrane assembly of the activated NADPH oxidase occurs, as described
in "Components and regulation of the phagocyte NADPH oxidase." The
known functional components involved in activation are shown: the
integral membrane cytochrome b558, consisting of the
gp91phox and p22phox
subunits; the cytosolic oxidase components
p47phox, p67phox, and
p40phox; and the Rac2 GTPase in complex with the
regulatory protein GDI (GDP dissociation inhibitor). Multiple
regulatory phosphorylations of p47phox are
depicted by the attached 4 P groups; this is not meant to indicate the
actual number of phosphorylation sites. Wavy line on Rac2 represents
the C-terminal geranylgeranyl isoprenyl group and associated polybasic
domain. Portions of this figure have been used in Diebold and
Bokoch.47
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p47phox is also known to be dispensable for
NADPH oxidase activity under cell-free conditions and appears to serve
primarily as an adapter in the intact cell to facilitate binding of
p67phox with cyt b in response to activating
stimuli.18,19 It should be emphasized that this adapter
function of p47phox is critical for normal NADPH
oxidase activation by stimuli in intact leukocytes, as evidenced by the
marked impairment in superoxide formation in chronic granulomatous
disease patients lacking
p47phox.1,2 In contrast to
p47phox, p67phox appears
to be an absolutely required component of the enzyme. An "activation
domain" has been identified in p67phox (amino
acid [aa] 199-210 and perhaps aa 187-193) that is required for stimulation of oxidant formation via cyt b in cell-free
systems.20,21 This domain has been reported to interact
directly with cyt b to regulate the transfer of electrons from NADPH to
cyt b- bound flavin (step 1).22
As indicated above, Rac GTPase is also a required component of the
active phagocyte NADPH oxidase (Figure 1). Upon cell activation, Rac
(Rac2 in human neutrophils) dissociates from a cytosolic complex with
guanosine diphosphate (GDP) dissociation inhibitor (GDI) by an
as yet undetermined mechanism. GDP is exchanged for GTP through the
action of a guanine nucleotide exchange factor(s) (GEF), which appears
to be membrane localized23; Rac, now in its
GTP-bound active form, becomes membrane associated.24 Rac supports NADPH oxidase activity only in its GTP-bound active
form25 (an exception to this has been
proposed26,27).
GTPases of the Rho family, including Rac2, contain 2 important regions
involved in guanine nucleotide triphosphate binding and interactions
with regulatory molecules and effectors. These are termed
switch I (or the "effector" domain), encompassing amino acid residues about 25 to 45, and switch II, which includes residues about 58 to 77. Only switch I undergoes extensive conformational changes upon GTP binding (there is evidence that the switch II domain
in Rac adopts very similar conformations in both the GDP- and GTP-bound
states28). A third region of potential importance in
molecular interactions of Rac is the insert helix unique to Rho family
GTPases (residues 120-137). This so-called "insert domain" does not
undergo nucleotide-dependent conformational change but is readily
solvent accessible for protein-protein interactions.
The GTP-dependence of NADPH oxidase activation indicates that the Rac
switch I domain is necessary for oxidase regulation. Consistent with
this, point mutations within Rac switch I were unable to support
oxidase activity.29,30 The finding that Rac binds directly
to p67phox (but not
p47phox) via the switch I domain provided
important insight into Rac function in the oxidase.31 It
was shown that the tetratricopeptide repeat (TPR) in the N-terminus of
p67phox was the site of Rac
binding,32 and this was confirmed upon determination of
the crystal structure of the Rac-p67(TPR) complex.33 The
structure revealed specific stabilizing interactions between p67phox and Rac, including amino acids A27 and
G30 of Rac and the TPR domain of p67phox, and
suggested the availability of the insert helix for possible additional
protein interactions. Several prior investigations had suggested a
requirement for the Rac insert domain in the activation of the NADPH
oxidase. Peptide walking experiments indicated that blocking the insert
domain of Rac abrogated NADPH oxidase activation.34 Studies using insert domain deletion mutants of Rac have yielded conflicting results, however, concluding either that the insert domain
was absolutely required35,36 or
unnecessary37,38 for Rac oxidase activity. Similarly, it
has been reported that the Rac1 insert region is either
essential39 or not required40 for mitogenesis
and ROS formation in fibroblasts.
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Current models of Rac function in NADPH oxidase regulation |
The role of Rac in controlling NADPH oxidase assembly and activity
appears to involve several components. While Rac does not directly
mediate the translocation of the cytosolic oxidase components p47phox and p67phox to
the membrane,15 Rac activation can induce NADPH oxidase assembly,41 perhaps indirectly through the action of
effector kinases such as p21-activated kinase.42 Data from
cell-free systems cited above indicate a distinct requirement for Rac
in the membrane-assembled oxidase as well. Currently, there are 3 major
molecular models to describe how Rac GTPase directly regulates activity
of the assembled NADPH oxidase complex.
The model proposed by Lambeth et al (Figure
2, model A) suggests that p67phox, containing a
defined activation domain for cyt b, is the only protein influencing
the rate-limiting electron transfer step (step1) of the NADPH oxidase
(reviewed by Lambeth2). Rac GTPase is activated (see
preceding sections) and is recruited to the plasma membrane via its
C-terminal prenyl group and polybasic domain. Rac is considered to act
solely as an adapter molecule that binds to
p67phox through the switch I region and aids in
the proper orientation of this active regulator of the system to cyt b.
The Rac insert domain may bind to cyt b but, as with
p47phox, this interaction serves only to
position and facilitate binding of p67phox to
cyt b. This aspect of the model is based on the observation that a
nonprenylated Rac1 mutant lacking the insert domain decreased the
affinity (median effective concentration [EC50])
of Rac for the oxidase but had no effect on the maximal rate,
Vmax, of superoxide production.36 Our laboratory, on the other hand, has
observed a decrease in Vmax when using a
prenylated Rac2 version of this mutant.35
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| Figure 2.
Comparison of proposed models
of NADPH oxidase regulation by Rac GTPase.
In each of the proposed molecular models for NADPH oxidase regulation
by Rac GTPase, the switch 1 region of Rac (not indicated) interacts
with p67phox, the prenylated tail and polybasic domain of
Rac (shown as a zigzag line) interact with the membrane, and the
activation domain of p67phox (a crosshatched section)
interacts with cytochrome b558. A role for
p40phox remains unclear. In the model of Lambeth and
colleagues (model A), Rac is thought to be recruited to the plasma
membrane phospholipid bilayer via its prenylated C-terminus and
polybasic domain. Indirect evidence supports the idea that the Rac
insert domain (hatched section) may interact directly with cytochrome
b558. Lambeth2 proposes the activation domain
of p67phox is the sole regulator of the electron transfer
step from NADPH to FAD. Rac and p47phox serve as adapters
aiding in the interaction of p67phox with cytochrome
b558. In model B proposed by Pick and
colleagues,37,38 Rac is thought to interact only with
plasma membrane phospholipids via its C-terminal prenyl group and
polybasic domain and does not interact physically with cytochrome
b558. In this model, the insert domain is not involved in
protein interactions or regulation of the NADPH oxidase. As in the
model of Lambeth and colleagues, p67phox is the sole
regulator of electron transfer by cytochrome b558, while
Rac and p47phox serve only as adapters to position
p67phox for interaction with cytochrome b558.
Diebold and Bokoch35 propose a 2-step model (model C) for
the regulation of NADPH oxidase by Rac. In step 1, Rac translocates to
the membrane and interacts with the phospholipid bilayer via its
prenylated/polybasic C-terminus. In addition, Rac, via its insert
domain, interacts with cytochrome b558 and contributes to
the regulation of electron flow from NADPH to FAD without interacting
with p67phox. p67phox is still required for
electron flow to occur in step1 and regulates electron flow via its
activation domain. The interaction of the insert domain of Rac with
cytochrome b558 may induce a conformational change in
cytochrome b558 that modulates the interaction of
p67phox and cytochrome b558. In step 2, the
interaction between the switch I domain of Rac and the Rac-binding
domain of p67phox, probably inducing a conformational
change in p67phox, is required for electrons to continue to
flow from FAD to the heme groups of cytochrome b558. (The
step 1 reaction only is depicted in models A and B because this is
thought to be the rate-limiting step in the overall electron transfer
pathway to molecular oxygen. The step 2 reaction does take place in all
3 models depicted.) Portions of this figure have been used in
Diebold and Bokoch.47
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The model suggested by Pick and colleagues (Figure 2, model B) is
similar to the Lambeth model in that p67phox
remains the primary regulator of the electron transfer reactions. As
with the Lambeth model, the Pick model portrays Rac and
p47phox as adapter molecules that aid
p67phox in binding to cyt b (discussed by
Gorzalczany et al43,44). However, this model opposes the
view that Rac interacts directly with cyt b and that the Rac insert
domain is important in oxidase regulation. Instead, they propose that
Rac interacts only with membrane phospholipids via the prenylated
C-terminus to "carry" p67phox into position
with cyt b. This postulate is based upon observations that prenylated
Rac can bind equally well to phospholipid vesicles either devoid of or
containing cyt b.43 In addition, Pick's group used
prenylated Rac1-p67phox chimeras in the
cell-free system and reported that deletion of the insert domain of
Rac1 did not affect the ability of this chimera to support superoxide
production.44 (Interestingly, this group of investigators
originally observed that peptides overlapping the insert domain of Rac
inhibited superoxide production in the cell-free
system.34) Consequently, based on these observations and
that by Lambeth's group that deletion of the insert domain does not
affect Vmax,36 the model of Pick et
al does not support a physical or functional interaction of Rac with
cyt b.
There are several observations that appear to be inconsistent with
aspects of the above models. First, it is possible to dissociate the
membrane translocation of Rac from that of
p67phox pharmacologically,15 which
is inconsistent with a required carrier function of Rac for
p67phox. Additionally, an effect of Rac mediated
solely through interactions with p67phox is
inherently problematic due to the low affinity of this interaction as
determined in vitro.31 With regard to a role of the Rac
insert domain, a careful examination of the data of Gorzalczany et
al44 shows that, in fact, there is a marked decrease
(> 60%) in the ability of the insert domain deletion mutant to
support oxidase activity at concentrations of chimera below 200 nM (ie,
within the normal physiologic range of reactants). Finally, based upon effects of exogenous Rac-GTP on the activity of various
Rac-p67phox chimeras, Pick has recently
suggested that Rac may play an additional role in modifying the active
conformation of p67phox.44
The regulatory model proposed by Diebold and Bokoch35
differs in several ways from the previous 2 models (Figure 2, model C).
First, it is proposed that there is differential regulation of the 2 steps involved in electron transfer from NADPH to molecular oxygen. Rac
is required apart from and in addition to
p67phox for the step 1 reaction. However, Rac
must subsequently then interact with p67phox for
the step 2 reaction to occur. This is based upon the observation that a
non Rac-binding p67phox aa 178 to 184 deletion
mutant could still support electron transfer from NADPH to FAD (step 1)
but not from FAD to cyt b (step 2). Of note, the basis for the loss of
interaction of this p67phox mutant with Rac is
not clear, because these residues are not directly involved in binding
interactions observed in the crystal structure.33 Our
laboratory has subsequently performed these same experiments with
p67phox mutated within the Rac-interacting TPR
domains, with similar results (B.A.D., G.M.B., unpublished
observations, June 2001). In support of this observation, the
reciprocal experiment utilizing the Rac2 D38A mutant that does not bind
p67phox also indicated independent roles for Rac
and p67phox in step 1 but not step 2 activity.
In contrast, the Rac2 insert domain was found to be critical for both
the step 1 and step 2 electron transfer reactions. This 2-step model is
consistent with kinetic analysis of oxidase activation45
and can explain the observation that neutrophils from a patient with a
gp91phox missense mutation were able to reduce
FAD but could not complete the reaction to transfer electrons to
molecular oxygen.46
Secondly, because Rac2 was operative in the absence of
p47phox, this suggested that Rac2 must interact
directly with cyt b to support the step 1 reaction. Indeed, the
intensity of a fluorescent analog of GppNHp (mant-GppNHp) bound to Rac2
increased in the presence of cyt b, indicating direct interaction
between Rac2 and cyt b. Use of the insert domain deletion mutant of
Rac2 in place of wild-type Rac2 eliminated this interaction, indicating that this domain was critical for cyt b binding. In support of the
fluorescence data, we have recently demonstrated that
glutathione-S-transferase (GST)-Rac2 can specifically bind cyt b
purified from neutrophils in pull-down assays (B.A.D., G.M.B.,
unpublished observations, April 2002). These data are
consistent with previous observations that membrane translocation of
Rac2 was decreased by 75% in neutrophils from cyt b-deficient CGD
patients.5 Overall, these data strongly indicate that the
Rac2 insert domain is necessary for both the functional and physical
interaction of Rac2 with cyt b.
It is clear that the 3 models differ in how they view oxidase
regulation by Rac GTPase: adapter versus active participant. It is not
clear at this point how the experimental data supporting each model can
be reconciled. At least part of the discrepancy between these models
may be in part due to the use of prenylated Rac versus nonprenylated
Rac in certain key experiments. The concentration of prenylated Rac
required in the cell-free system is at least 100-fold less than
nonprenylated Rac. The use of high concentrations of unprocessed GTPase
may obscure relevant high-affinity protein-protein interactions that
normally occur at physiologic concentrations of reactants within the
plane of the membrane. Ultimately, understanding the complete
mechanism(s) through which Rac controls NADPH oxidase activity will
depend upon additional in vitro biochemical studies combined with
intact cell studies using neutrophils and other leukocytes or
leukocytic cell lines.
With regard to the regulation of ROS in nonphagocytic cells, there
interestingly is little rigorous evidence supporting the existence of
p67phox and p47phox in
most nonleukocytic cells. This suggests that either some other protein(s) serves the normally essential regulatory function of p67phox in the nonphagocyte system or that Nox
regulation does not require this oxidase component. It is therefore not
clear to what extent the regulation of Nox proteins will be similar to
regulation of the phagocyte NADPH oxidase. However, the model proposed
by Diebold and Bokoch35 does suggest a minimal means
whereby Rac might directly regulate superoxide production by Nox
proteins through a mechanism similar to Rac binding and regulation of
cyt b in phagocytes. In this light, understanding how Rac GTPase
regulates the NADPH oxidase of phagocxytic leukocytes may provide the
basic insights necessary to develop therapeutic means to intervene in ROS-related pathological disease states in both inflammatory and noninflammatory cells.
| |
Footnotes |
Submitted April 16, 2002; accepted June 4, 2002.
Prepublished online as
Blood First Edition Paper, June 21, 2002; DOI
10.1182/blood-2002-04-1149.
Reprints: Gary M. Bokoch, Department of Immunology, The
Scripps Research Institute, 10666 N Torrey Pines Road, IMM-14, La
Jolla, CA 92037; e-mail: bokoch{at}scripps.edu.
| |
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Top
Abstract
Introduction