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MICROSCOPY RESEARCH AND TECHNIQUE 47:107–113 (1999)
Wiskott-Aldrich Syndrome: A Disorder of Haematopoietic
Cytoskeletal Regulation
ADRIAN J. THRASHER* AND SIOBHAN BURNS
Molecular Immunology Unit, Institute of Child Health, London WC1N 1EH, United Kingdom
KEY WORDS
WASp; SCAR; Arp2/3; chemotaxis; filopodia; macrophage; dendritic cell
ABSTRACT
The Wiskott-Aldrich Syndrome (WAS) is a rare inherited X-linked recessive disease
characterised by immune dysregulation and microthrombocytopenia. Recently, the biological
mechanisms that are responsible for the pathophysiology of WAS have been shown to be linked to
the regulation of the actin cytoskeleton in haematopoietic cells. The WAS protein (WASp) is now
known to be a member of a unique family that share similar domain structures, and that are
responsible for transduction of signals from the cell membrane to the actin cytoskeleton. The
interactions between WASp, the Rho family GTPase Cdc42, and the cytoskeletal organising complex
Arp2/3 are probably critical to many of these functions, which, when disturbed, translate into
measurable defects of cell polarisation and motility. Microsc. Res. Tech. 47:107–113, 1999.
r 1999 Wiley-Liss, Inc.
PHENOTYPIC FEATURES OF THE
WISKOTT-ALDRICH SYNDROME
The Wiskott-Aldrich Syndrome (WAS) is a rare inherited X-linked recessive disease characterised by immune dysregulation and microthrombocytopenia
(Wiskott, A, 1939; Aldrich, 1954; Remold O’Donnell,
1996; MIM 301000). The clinical phenotype of the
immune disorder includes susceptibility to pyogenic,
viral, and opportunistic infections, and eczema (Sullivan, 1994). Unlike thrombocytopenia, which is present
at birth, the immunological manifestations are progressive, with decreasing numbers of T lymphocytes (particularly CD8 cells) during early childhood, defects in
proliferative and delayed type hypersensitivity responses, and deficient production of antibodies to both
polysaccharide and protein antigens. Later complications to arise from this process include autoimmune
and lymphoproliferative disease. In its mildest form,
known as X-linked thrombocytopenia (XLT), mutations
in the same gene produce the characteristic platelet
abnormality but minimal immunological disturbance
(Villa, 1995; MIM 313900).
WISKOTT-ALDRICH SYNDROME PROTEIN
(WASp) IS A MEMBER OF A LARGER FAMILY
Although abnormalities of platelet structure, and the
presence of dysmorphic microvilli on the surface of WAS
T lymphocytes and T lymphocyte cell lines, suggested
an underlying cytoskeletal abnormality, it was not until
the gene was cloned in 1994 (gene bank accession
number U12707) that it became possible to examine
intimate biochemical interactions within the cell (Derry
et al., 1994; Gallego et al., 1997; Kenney et al., 1986;
Molina et al., 1992). The WAS gene is now known to
encode a 502 amino acid proline-rich intracellular
protein (WASp) expressed exclusively in haematopoietic cells, which belongs to a recently defined family of
more widely expressed proteins involved in transduction of signals from receptors on the cell surface to the
actin cytoskeleton. Other members of the family inr 1999 WILEY-LISS, INC.
clude neural (N)-WASp, SCAR (suppressor of G-protein
coupled cyclic-AMP receptor cAR, isolated from Dictyostelium), four human SCAR proteins (hsSCAR1–4),
other homologues of SCAR (in mouse, Caenorhabditis
elegans, and Drosophila), and the WASp-related S.
cerevisiae protein Las17p/Bee1p (Bear et al., 1998; Li,
1997; Miki et al., 1996).
DOMAIN ORGANISATION OF WASp AND
RELATED PROTEINS
WASp, N-WASp, SCAR, and Las17p/Bee1p are organised into modular domains defined by sequence homology and binding interactions (see Fig. 1). They all
posses C-terminal polyproline ‘‘P’’, Wiskott-homology
(WH)-2 and acidic ‘‘A’’ domains. N-WASp, has a similar
domain structure to WASp, but has an additional IQ
motif in the N-terminal half of the protein, which binds
calmodulin light chains. Although first identified as a
Grb2-binding protein in bovine brain, N-WASp is widely
expressed (Miki et al., 1996). SCAR family proteins are
homologous to each other in the N-terminus (SCAR
homology domain, SHD), but differ in this region from
WASp and N-WASp and lack typical PH and CRIB
domains. However, they retain a basic domain ‘‘B’’
upstream of the ‘‘P’’ region (Bear et al., 1998). Las17p/
Bee1p has a similar domain structure to WASp and
N-WASp except for the absence of a recognisable CRIB
domain (Li, 1997).
Pleckstrin Homology (PH) Domain
For N-WASp, a Pleckstrin homology (PH)-domain
has been assigned to the N-terminus overlapping a
WASp-homology1 (WH1) 1-domain. The WH1 domain
has been identified in several proteins including vasodilator-stimulated phosphoprotein (VASP), Dena (Drosophila-enabled), Mena, Homer, and Ev1, all of which
*Correspondence to: Adrian J. Thrasher, Molecular Immunology Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. E-mail:
a.thrasher@ich.ac.uk
Received 11 Aprril 1999; accepted in revised form 25 May 1999
108
A.J. THRASHER AND S. BURNS
Fig. 1. Domain structure of WASp: see text for full explanation. For
the related protein, N-WASp, a putative N-terminal Pleckstrin homology (PH)-domain, binds to the acidic phospholipid phosphatidylinositol (4,5)-bis-phosphate (PIP2), and could therefore facilitate localisation to the cell membrane. An undefined region in the N-terminal half
also binds to Wiskott-interacting protein (WIP), which itself may be
regulated by Src-homology (SH)-3 containing signaling molecules, and
may also bind to actin directly. One of the most important functions of
WASp, mediated through a Cdc42/Rac interactive binding (CRIB)
motif, is to act as an effector for the cytoskeletal regulator Cdc42,
which is known to induce the formation of focal adhesion complexes
have been implicated in the regulation of the actin
cytoskeleton (Callebaut et al., 1998; Gertler et al., 1996;
Ponting and Phillips, 1997). Although the function of
the PH-domain has not been defined for WASp, this
type of domain may well be important for interaction
with other proteins or lipids. For the related protein
N-WASp, the N-terminal PH-domain has been shown to
bind the acidic phospholipid phosphatidylinositol (4,5)bis-phosphate (PIP2), and through this interaction
could allow N-WASp or WASp to localise at the cell
membrane (Lemmon et al., 1996; Miki et al., 1996).
However, careful alignment of the WASp PH-domain to
a defined consensus has recently shown that only 9 out
of 94 amino acids are identical, casting doubt on its
existence (Insall and Machesky, in press; Musacchio et
al., 1993). Furthermore, the related protein Las17p/
Bee1 cannot contain a PH-domain as the initiation
codon occurs at a site within the PH-domain itself
(Insall and Machesky, in press).
and filopodial extensions. The activity of WASp may also be critically
regulated by cytosolic signaling molecules binding to a proline-rich
region (PPPPP). The effector function of WASp is probably mediated
through the C-terminal region, which includes a Wiskott homology
domain (WH2), and an acidic ‘‘A’’ region that binds to p21-Arc of the
Arp2/3 complex. In the inactive state, the ‘‘A’’ region may form an
intramolecular interaction with a basic ‘‘B’’ region. In the event of
activation, the ‘‘A’’ region would become available for interaction with
the Arp2/3 complex, which, it is suggested, mediates the assembly of
branching filaments from monomeric actin bound to the WH2 domain.
CDC42/Rac Interactive Binding (CRIB) Motif
The first real biochemical evidence to implicate WASp
in the regulation of the actin cytoskeleton came from
studies in which WASp was shown to cluster physically
with polymerised actin. In addition, WASp bound specifically to the GTP-bound form of the Rho-like GTPase
Cdc42, and less well to GTP-bound Rac, suggesting that
it acts as a direct effector molecule for Cdc42 (Aspenstrom et al., 1996; Kolluri et al., 1996; Symons et al.,
1996). Cdc42 belongs to the Rho family of small GTPbinding proteins, and regulates the formation of distinct actin-filament containing protrusions known as
filopodia in fibroblast and monocytic cell lines (Allen et
al., 1997; Kozma et al., 1995; Nobes and Hall, 1995).
More recently, N-WASp has been shown to potentiate
the formation of Cdc42-induced filopodia in microinjected COS and Swiss 3T3 cells (Miki et al., 1998). In
contrast, growth factor-induced activation of the re-
ROLE OF WASp IN CYTOSKELETAL FUNCTIONS.
lated GTP-binding protein Rac leads to accumulation of
an actin network at the cell periphery producing lamellapodia and membrane ruffling (Lamarche et al., 1996;
Ridley et al., 1992). Cdc42 and Rac have also been
shown to participate in the formation of cell-substratum focal adhesion complexes distinct from Rhoinduced focal adhesions (Nobes and Hall, 1995). For
both WASp and N-WASp, the interaction with Cdc42/
Rac has been shown to be mediated through a Cdc42/
Rac small GTPase interactive binding (CRIB) motif (or
GTPase binding domain, GBD), which is found in many
downstream effectors of Cdc42 and Rac, although regions outside this motif are necessary for structure
formation and for tight interaction (Rudolph et al.,
1998). Some clues to the cellular pathophysiology of
WAS can, therefore, be obtained from work, implicating
Cdc42 both as a regulator of actin-containing filopodial
extensions, as well as in the development of cell polarity
in budding yeast and murine T lymphocyte hybridoma
cells, Fc-receptor mediated phagocytosis, and macrophage chemotaxis (Adams et al., 1990; Allen et al.,
1998; Caron and Hall, 1998; Johnson and Pringle, 1990;
Kozma et al., 1995; Massol et al., 1998; Nobes and Hall,
1995; Stowers et al., 1995).
Proline-Rich ‘‘P’’ Domain
WASp has been shown by several groups to bind SH3
domains of cytosolic signalling molecules, although the
significance of many of these in vitro associations is
unclear (Brickell et al., 1998). More convincingly, in
vivo binding interactions have been shown for the
adapter proteins Nck and Grb2, the protein tyrosine
kinase Fyn, a cytoplasmic protein-tyrosine kinase of
the c-Src family, which may participate in regulation of
cytoskeletal architecture, and the B cell Tec family
tyrosine kinase, Btk (Baba, 1999; Banin et al., 1996;
Rivero et al., 1995; She et al., 1997). More recently, a
cytoskeletal-associated protein related to Schizosaccharomyces pombe cytokinetic cleavage furrow regulatory
protein (CDC15p), known as proline-serine-threonine
phosphatase-interacting protein (PSTPIP), has been
shown to interact directly with WASp and to inhibit
WASp-induced actin bundling activity in vivo in a
process that is regulated by tyrosine phosphorylation of
the SH3 domain (Wu et al., 1998). The interaction
between WASp and SH3 domains is mediated by polyproline P stretches rich in the SH3 binding motif PXXP.
WASp Interacting Protein (WIP)
Another proline-rich protein, WASp-interacting protein (WIP), has recently been shown to co-immunoprecipitate with WASp from lymphocyte cell lysates (although it is ubiquitously expressed, and may, therefore,
also interact with other members of the WASp family)
(Ramesh et al., 1997). Two verprolin homology domains
at the N-terminus of WIP, suggest that it may interact
directly with actin, while the presence of SH3-binding
motifs could provide a link with other cellular signalling pathways. The region of binding to WASp has not
been accurately identified, although it appears to require N-terminal sequences distinct from the CRIB
domain.
109
Carboxy Terminal Binding Domains
The carboxy terminal regions of WASp, N-WASP, and
SCAR contain an actin-binding region known as WH2
or verprolin homology (VH) domain, and a cofilin
homology domain that may participate in depolymerisation of actin filaments (Miki et al., 1996, 1998). Carboxyterminal of the WH2 domain lies a conserved series of
acidic residues ‘‘A’’, which recently have been shown to
be necessary for the binding (probably mediated by
p21-Arc) of actin-related proteins of a cytoskeletal
organiser known as the Arp2/3 complex (Machesky and
Insall, 1998). The Arp2/3 complex consists of 7 proteins
including the actin-related proteins Arp2 and Arp3, and
other components p41-Arc, p34-Arc, p21-Arc, p20-Arc,
and p16-Arc (Welch et al., 1997a). This complex is
localised to areas of active actin polymerisation, such as
in lamellipodia and at the base of filopodia. It has also
been shown to initiate actin polymerisation on the
surface of the motile intracellular pathogen Listeria
Monocytogenes and may, therefore, be essential for the
initiation or formation of actin tails that propel the
organism through the cytosol (Welch et al., 1997b). In
vitro the complex has been shown to nucleate new actin
filaments, a process that is considerably enhanced
when bound to WASp-family proteins (Machesky and
Insall, 1998; Machesky et al., 1999; Mullins et al., 1998;
Rohatagi et al., 1999). Overexpression of the conserved
C-terminal acidic domain (but not the WH2 domain
alone) of WASp and SCAR disrupts the localisation of
the Arp2/3 complex, inhibits lammellipodia and stress
fibre formation in Swiss 3T3 cells in response to plateletderived growth factor (PDGF) and sphingosine 1-phosphate, respectively, and inhibits endogenous filopodia
formation in J774 macrophages, suggesting that WASprelated proteins regulate the cytoskeleton through this
complex. It is, therefore, possible that the Arp2/3 complex becomes activated on binding to WASp and mediates the regulated assembly of actin filaments from
monomeric actin bound to the WH2 domain of WASp.
An additional possibility is that the C-terminal acidic
domain binds to a basic domain upstream of CRIB (in
WASp and N-WASp) and upstream of the ‘‘P’’ region (in
SCAR), thereby masking binding sites for Arp2/3, which
only become available when GTP-bound Cdc42 or relevant SH3 domains interact with WASp (Miki et al.,
1998).
WASp family proteins also interact with the small
actin monomer binding protein profilin, although the
nature of this interaction in terms of the binding
residues, and whether it is direct or mediated through
an intermediate such as the Arp2/3 complex are unknown.
Cytoskeletal Disturbances in WAS
The generation of regulated immune responses is
dependent on the ability of cells to migrate in response
to integrated chemical signals (reviewed in Baggiolini,
1998). In addition to the influx of effector cells to sites of
inflammation, these processes are responsible for the
relocation of dendritic cells from their surveillance
positions in non-lymphoid tissue to the secondary lymphoid organs, and migration of lymphocytes into specialised B and T cell zones (Banchereau and Steinmann,
1998). The maintenance of a normal immune repertoire
110
A.J. THRASHER AND S. BURNS
also depends on the ability of thymic emigrants to
interact in some way with MHC molecules expressed on
peripheral dendritic cells, and the same may be true for
the persistence of mature B cells, although the existence and location of a ligand to provide the necessary B
cell receptor signal remains uncertain (Brocker et al.,
1997; Lam et al., 1997; Rooke et al., 1997; Takeda et al.,
1996; Tanchot et al., 1997). The cell biological mechanisms that allow these trafficking processes to occur
are, therefore, intimately related to the regulation of
the cytoskeletal architecture, and the response of this
to external stimuli is of fundamental importance to
immune cell homeostasis, and the initiation of inflammatory processes. Cells from patients with WAS provide natural models with which some questions about
cytoskeletal regulation can be answered. While mutations restricted to the first three exons of the WAS gene
may lead to a mild clinical phenotype and expression of
residual protein, in the majority of cases WASp is
destabilised, and most patients are effectively null
mutants (MacCarthy-Morrogh et al., 1998).
Abnormalities of Immune Cell Chemotaxis and
Chemokinesis
Disturbance of cellular processes that are directly
related to re-organisation of cytoskeletal architecture,
such as those directing cell motility, could contribute
significantly to the immunopathology of WAS. To investigate the effects of WAS mutation on cell motility, we
used a direct-viewing chemotaxis chamber to analyse
chemotactic responses of WAS neutrophils and macrophages migrating on serum-coated glass surfaces in
stable linear concentration gradients of diffusable attractants. Chemotaxis of macrophages (to CSF-1) but
not of neutrophils (to fMLP or IL-8) was found to be
abolished in all cases, whereas the speed of random
motility of both cell types was found to be indistinguishable from control cells (Zicha et al., 1998). Similar
disturbances of motility in WAS cells have been reported elsewhere (Badolato et al., 1998). Furthermore,
polymerisation of actin on the ventral surface of WAS
macrophages and extension of filopodia were both
found to be severely compromised, adding further support to the role of WASp as an effector for Cdc42 in
haematopoietic cells (Thrasher and Jones, unpublished
results). Interestingly, Bac1 rodent macrophages microinjected with a dominant negative Cdc42 mutant
(N17Cdc42) have been shown to have specific defects of
polarisation and chemotaxis identical to those of WAS
mutant macrophages (Allen et al., 1998). The effects of
this disturbance on the localisation of Arp2/3 complex
are currently being investigated. The apparent functional normality of neutrophils in terms of both chemotaxis and chemokinesis could be explained by the use of
alternative WASp family proteins such as SCAR for
G-protein coupled signalling, and is supported by the
fact that expression of WASp is virtually undetectable
in this cell type (Thrasher, unpublished results).
A major contribution to the immune dysregulation of
WAS could arise from the inability of specialised antigen presenting cells known as dendritic cells (DCs) to
traffic normally between non-lymphoid tissues and T
lymphocyte-rich areas of lymphoid organs (Banchereau
and Steinmann, 1998; Thrasher et al., 1998). In similar
motility experiments to those conducted on macro-
phages and neutrophils, WAS DCs exhibited major
abnormalities in the distribution of the peripheral
filamentous F-actin cytoskeleton (see Fig. 2), failed to
develop normal polarised morphologies or to extend
dendritic processes on a fibronectin substratum, and
were essentially immotile when stimulated with fMLP
or RANTES (Binks et al., 1998). In contrast, formation
of membrane ruffles, presumably mediated by Rac,
appeared to be quantitatively and qualitatively preserved. WAS macrophages tested under the same conditions showed identical defects in cell motility, suggesting that both these cell types are compromised at least
at two levels (Thrasher and Jones, unpublished data).
Firstly, the cells are unable to respond to chemical
stimuli in a directional manner, even though they
appear to activate normally. These disturbances probably relate to abnormalities of Cdc42-WASp-mediated
filopodia formation, and are consistent with recent
suggestions that these structures are essential for
macrophage chemotaxis (Allen et al., 1997, 1998). At a
second level, WAS macrophages and DCs polarise poorly
and are unable to translocate when adherent to surfaces that require engagement of integrins on the cell
surface. The precise mechanisms by which WASp directs this process are unclear at present, but dysfunctional interaction between anchoring integrins, the
cytoskeleton, and intracellular myosin-generated forces,
may restrict the capacity of the cell to achieve both
spatial asymmetry and contractile movement.
As WASp is expressed in all haematopoietic cells,
similar abnormalities of cell traffic may be apparent in
other haematopoietic lineages. For lymphocytes, the
gross morphological disturbances of surface microvilli
suggest that dysmotility similar to that of macrophages
and DCs could also be present. Preliminary data obtained from WASp mutant mice generated by gene
targeting suggests that this may well be the case
(Snapper et al., 1998; Snapper and Rosen, 1999). In
addition, WAS carrier females almost universally exhibit non-random X-inactivation patterns in CD34⫹
progenitors, indicating that WASp must also be functional even at this level. On the basis of our own
experiments that demonstrate that WASp is expressed
in intra-aortic CD34⫹ cell clusters at the aorta-gonadmesonephros (AGM) stage of human embryonic haematopoiesis, WAS stem cells may be less able than their
normal equivalents to seek out the appropriate microenvironmental niches in which liver, and later bone
marrow, haematopoiesis is established (Thrasher and
Marshall, unpublished results). This is reminiscent of
mice lacking the chemokine receptor CXCR4 or its
ligand SDF-1, which have markedly impaired colonisation of bone marrow by multipotent haematopoietic
cells, and murine ␤1 integrin –/– integrin chimeras,
which do not develop definitive liver haematopoiesis
due to a failure to seed this tissue during embryonic
development (Fassler and Meyer, 1995; Nagasawa et
al., 1996; Zou et al., 1998).
Abnormalities of Other Cytoskeletal
Related Functions
In addition to gross defects of cell motility, it is likely
that WASp is important for the regulation of the
cytoskeleton in other processes such as lymphocyte
activation and phagocytosis. For example, Cdc42-
ROLE OF WASp IN CYTOSKELETAL FUNCTIONS.
111
Fig. 2. WAS dendritic cells. a: WAS DCs
derived in vitro from CD14⫹ peripheral blood
precursors and stained with TRITC-phalloidin on a fibronectin substratum. Compared to
normal DCs (b), WAS cells have a poorly
defined cytoskeletal structure, and lack typical podosomal structures on the ventral surface.
mediated actin polymerisation has also been shown to
be necessary for promoting the correct orientation of
lymphocytes and antigen presenting cells (Stowers et
al., 1995). Following activation of lymphocytes, an
asymmetric assembly of receptors and signalling molecules known as the Cap forms on the cell surface
(reviewed in Penninger and Crabtree, 1999). In addition, interaction between T lymphocytes and antigen-
presenting cells results in the formation of highly
organised clusters of antigen receptors, coreceptors,
adhesion, and signalling molecules (supramolecular
activation clusters, SMAC), a process that requires
actin polymerisation. The segregation of these molecules within SMACs is critical for the initiation of
physiological immune responses. T cells from WAS
patients and WAS mutant mice generated by gene
112
A.J. THRASHER AND S. BURNS
targeting both show abnormalities of antigen receptor
stimulated proliferation, and in the mice of antigen
receptor Cap formation (Molina et al., 1993; Snapper et
al., 1998). In contrast, studies on murine WAS B cells
have demonstrated normal proliferation, and normal
Cap formation, suggesting that there may be functional
redundancy in this cell type, although defects in proliferative responses of human WAS B cells have been
reported previously (Facchetti et al., 1998; Simon et al.,
1992; Snapper et al., 1998).
Recently, several groups have shown that Fc␥ receptor (Fc␥R)-mediated phagocytosis is regulated by Cdc42
and Rac1 (Caron and Hall, 1998; Cox et al., 1997;
Massol et al., 1998;). It also seems likely that Cdc42 and
Rac1 have distinct non-overlapping functions that act
co-operatively in the formation of the phagocytic cup. In
one study, two distinct mechanisms of phagocytosis
were identified (Caron and Hall, 1998). One used by the
immunoglobulin receptor Fc␥R was mediated by Cdc42
and Rac1 whereas that used by the complement receptor (CR3) was mediated by Rho. In addition, microinjection of the WASp CRIB domain (as a competitor for
Cdc42 effectors) into J774 macrophages completely
prevented Fc␥R-mediated phagocytosis. More recently,
we have found that Fc␥R-mediated phagocytosis is
impaired in WAS macrophages, but remains intact in
neutrophils, adding further support to the suggestion
that related proteins are functional in this cell type
(Thrasher and Lorenzi, unpublished data).
Platelet Abnormalities in WAS
The mechanism of the platelet defects in WAS are
largely unknown. However, it appears likely that WASp
is involved in the formation of platelets from megakaryocytes, in the maintenance of platelet integrity in the
circulation, and in platelet aggregation at sites of tissue
injury. As shown for other cell types in WAS, these
processes may be linked to abnormalities of filopodial
extension.
CONCLUSIONS
The ability to study WAS mutant cells provides a
unique opportunity to unravel some of the mechanisms
of actin polymerisation in the haematopoietic system.
The cellular phenotype of WAS clearly demonstrates
that defects in the regulation of cytoskeletal architecture have profound effects on the motile and morphological characteristics of cells that initiate and regulate
immune responses. The extent to which these defects
operate in vivo is under investigation, and will be
greatly facilitated by the development of murine models of WAS. In addition, processes unrelated to chemokinesis, for example, antigen-mediated lymphocyte activation and phagocytosis of either microorganisms or
apoptotic cells, may be critically dependent on normal
WASp function. Understanding the way in which WASp
participates in these processes will enhance our understanding of cytoskeletal biology, and hopefully will
translate into the development of new treatments for
this disease.
ACKNOWLEDGMENTS
A.J.T. is a Wellcome Clinical Scientist, and S.B. is a
Wellcome Clinical Training Fellow. We are grateful for
help and advice from Professor Gareth Jones, Professor
Paul Brickell, Professor David Katz, and Professor
Christine Kinnon.
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