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PubMed2006

A role for PKCtheta in outside-in alpha(IIb)beta3 signaling.

Fibrinogen binding to platelets triggers alpha(IIb)beta3-dependent outside-in signals that promote actin rearrangements and cell spreading. Studies with chemical inhibitors or activators have implicated protein kinase C (PKC) in alpha(IIb)beta3 function. However, the role of individual PKC isoforms is poorly understood. Biochemical and genetic approaches were used to determine whether PKCtheta is involved in alpha(IIb)beta3 signaling. PKCtheta was constitutively associated with alpha(IIb)beta3 in human and murine platelets. Fibrinogen binding to alpha(IIb)beta3 stimulated the association of PKCtheta with tyrosine kinases Btk and Syk, and tyrosine phosphorylation of PKCtheta, Btk and the actin regulator, Wiskott-Aldrich syndrome protein (WASP). Mouse platelets deficient in PKCtheta or Btk failed to spread on fibrinogen. Furthermore, PKCtheta was required for phosphorylation of WASP-interacting protein on Ser-488, an event that has been linked to WASP activation of the Arp2/3 complex and actin polymerization in lymphocytes. Neither PKCtheta nor Btk were required for agonist-induced inside-out signaling and fibrinogen binding to alpha(IIb)beta3. Thus, PKCtheta is a newly identified, essential member of a dynamic outside-in signaling complex that includes Btk and that couples alpha(IIb)beta3 to the actin cytoskeleton.

Actins↗

PubMed2001

Structure of Arp2/3 complex in its activated state and in actin filament branch junctions.

The seven-subunit Arp2/3 complex choreographs the formation of branched actin networks at the leading edge of migrating cells. When activated by Wiskott-Aldrich Syndrome protein (WASp), the Arp2/3 complex initiates actin filament branches from the sides of existing filaments. Electron cryomicroscopy and three-dimensional reconstruction of Acanthamoeba castellanii and Saccharomyces cerevisiae Arp2/3 complexes bound to the WASp carboxy-terminal domain reveal asymmetric, oblate ellipsoids. Image analysis of actin branches indicates that the complex binds the side of the mother filament, and Arp2 and Arp3 (for actin-related protein) are the first two subunits of the daughter filament. Comparison to the actin-free, WASp-activated complexes suggests that branch initiation involves large-scale structural rearrangements within Arp2/3.

Acanthamoeba↗

PubMed2006

PTP-H2 and PTP-H3 from Microplitis demolitor Bracovirus localize to focal adhesions and are antiphagocytic in insect immune cells.

Viruses in the family Polydnaviridae are symbiotically associated with parasitoid wasps. Wasps inject polydnaviruses (PDVs) when laying an egg into their insect host, and expression of viral gene products causes several physiological alterations, including immunosuppression, that allow the wasp's progeny to develop. As with other PDVs, most Microplitis demolitor bracovirus (MdBV) genes are related variants that form gene families. The largest MdBV gene family includes 13 members that encode predicted proteins related to protein tyrosine phosphatases (PTPs). Sequence analysis during the present study indicated that five PTP family members (PTP-H2, -H3, -N1, and -N2) have fully conserved catalytic domains, whereas other family members exhibited replacements, deletions, or rearrangements of amino acids considered essential for tyrosine phosphatase activity. Expression studies indicated that most MdBV PTP genes are expressed in virus-infected host insects, with transcript abundance usually being highest in hemocytes. MdBV-infected hemocytes also exhibited higher levels of tyrosine phosphatase activity than noninfected hemocytes. We produced expression constructs for four of the most abundantly expressed PTP family members and conducted functional studies with hemocyte-like Drosophila S2 cells. These experiments suggested that recombinant PTP-H2 and PTP-H3 are functional tyrosine phosphatases whereas PTP-H1 and PTP-J1 are not. PTP-H2 and -H3 localized to focal adhesions in S2 cells, and coexpression with another MdBV gene product, Glc1.8, resulted in complete inhibition of phagocytosis.

Animals↗

PubMed2001

Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins.

Actin filament assembly and turnover drive many forms of cellular motility, particularly extension of the leading edge of locomoting cells and rocketing of pathogenic microorganisms through host cell cytoplasm. De novo nucleation of actin filaments appears to be required for these movements. A complex of seven proteins called Arp2/3 complex is the best characterized cellular initiator of actin filament nucleation. Arp2/3 complex is intrinsically inactive, relying on nucleation promoting factors for activation. WASp/Scar family proteins are prominent cellular nucleation promoting factors. They bring together an actin monomer and Arp2/3 complex in solution or on the side of an existing actin filament to initiate a new filament that grows in the barbed end direction. WASp and N-WASP are intrinsically autoinhibited, and their activity is regulated by Rho-family GTPases such as Cdc42, membrane polyphosphoinositides, WIP/verprolin, and SH3 domain proteins. These interactions provide a final common pathway for many signaling inputs to regulate actin polymerization. Microorganisms either activate Arp2/3 complex directly or usurp N-WASP to initiate actin polymerization.

Actin Cytoskeleton↗

PubMed2003

A defect in hematopoietic stem cell migration explains the nonrandom X-chromosome inactivation in carriers of Wiskott-Aldrich syndrome.

A defect in cell trafficking and chemotaxis plays an important role in the immune deficiency observed in Wiskott-Aldrich syndrome (WAS). In this report, we show that marrow cells from WAS protein (WASP)-deficient mice also have a defect in chemotaxis. Serial transplantation and competitive reconstitution experiments demonstrated that marrow cells, including hematopoietic progenitors and stem cells (HSCs), have decreased homing capacities that were associated with a defect in adhesion to collagen. During development, HSCs migrate from the liver to the marrow and the spleen, prompting us to ask if a defect in HSC homing during development may explain the skewed X-chromosome inactivation in WAS carriers. Preliminary evidence has shown that, in contrast to marrow progenitor cells, fetal liver progenitor cells from heterozygous females had a random X-chromosome inactivation. When fetal liver cells from WASP-carrier females were injected into irradiated recipients, a nonrandom inactivation of the X-chromosome was found at the level of hematopoietic progenitors and HSCs responsible for the short- and long-term hematopoietic reconstitution. Therefore, the mechanism of the skewed X-chromosomal inactivation observed in WAS carriers may be related to a migration defect of WASP-deficient HSCs.

Actins↗

PubMed2003

Differential contribution of Wiskott-Aldrich syndrome protein to selective advantage in T- and B-cell lineages.

Somatic mosaicism because of in vivo reversion has been recently reported in a small number of patients affected with Wiskott-Aldrich syndrome (WAS). Flow cytometry analysis of WAS protein (WASP) expression has shown that these patients carried revertant cells only among T lymphocytes. Here, we have used high-resolution capillary electrophoresis to analyze genomic DNA from highly purified cells of one of these patients and detected revertant sequences also within the B-cell fraction. The demonstration of revertant cells among both T and B lymphocytes in this patient is consistent with the reversion event having occurred in a common lymphoid progenitor. However, although WASP-expressing T cells showed selective advantage and were readily detectable in the periphery of the mosaic patient, revertant B lymphocytes remained below the detection threshold of flow cytometry. These findings suggest that, contrary to T cells, differentiation and survival of B lymphocytes is minimally dependent on WASP.

B-Lymphocytes↗

PubMed2003

Essential role of the C. elegans Arp2/3 complex in cell migration during ventral enclosure.

Migration of cells through the reorganization of the actin cytoskeleton is essential for morphogenesis of multicellular animals. In a cell culture system, the actin-related protein (Arp) 2/3 complex functions as a nucleation core for actin polymerization when activated by the members of the WASP (Wiskott-Aldrich syndrome protein) family. However, the regulation of cell motility in vivo remains poorly understood. Here we report that homologues of the mammalian Arp2/3 complex and N-WASP in Caenorhabditis elegans play an important role in hypodermal cell migration during morphogenesis, a process known as ventral enclosure. In the absence of one of any of the C. elegans Arp2/3 complex subunits (ARX-1, ARX-2, ARX-4, ARX-5, ARX-6 or ARX-7) or of N-WASP (WSP-1), hypodermal cell migration led by actin-rich filopodia formation is inhibited during ventral enclosure owing to the reduction of filamentous actin formation. However, there is no effect on differentiation of hypodermal cells and dorsal intercalation. Disruption of the function of ARX-1 and WSP-1 in hypodermal cells also resulted in hypodermal cell arrest during ventral enclosure, suggesting that their function is cell autonomous. WSP-1 protein activated Arp2/3-mediated actin polymerization in vitro. Consistent with these results, the Arp2/3 complex and WSP-1 colocalized at the leading edge of migrating hypodermal cells. The stable localization of WSP-1 was dependent on the presence of Arp2/3 complex, suggesting an interaction between the Arp2/3 complex and WSP-1 in vivo.

Actin-Related Protein 2↗

PubMed2005

NOSTRIN functions as a homotrimeric adaptor protein facilitating internalization of eNOS.

Intracellular trafficking of endothelial nitric oxide synthase (eNOS) between different compartments is incompletely understood. Recently, we described a novel eNOS-interacting protein, NOSTRIN, which upon overexpression drives eNOS away from the plasma membrane towards intracellular compartments. Sequence similarity of NOSTRIN and pacsins/syndapins suggested a role for NOSTRIN in endocytosis. Accordingly, we show here that NOSTRIN interacts with the large GTPase dynamin and the actin nucleation promoting factor N-WASP by means of its SH3 domain, which also represents the docking site for eNOS. Via a coiled-coil region in the C-terminal portion of the protein, NOSTRIN oligomerizes, mainly forming trimers, which would allow simultaneous interaction with multiple binding partners of the SH3 domain. Consistent with this notion, expression of dynamin-2-GFP in CHO cells stably expressing eNOS (CHO-eNOS) results in recruitment of eNOS to dynamin-positive structures, only when NOSTRIN is present as well. Similarly, when N-WASP-GFP and NOSTRIN are co-expressed in CHO-eNOS cells, both proteins strongly co-localize with eNOS and are recruited to structures running along actin filaments. If, however, the actin cytoskeleton is depolymerized by cytochalasin D, NOSTRIN and eNOS are associated with extended structures in the cell periphery, possibly being unable to leave the plasma membrane. Together, these results indicate that NOSTRIN may facilitate endocytosis of eNOS by coordinating the function of dynamin and N-WASP.

Actins↗

PubMed2005

A WAVE2-Abi1 complex mediates CSF-1-induced F-actin-rich membrane protrusions and migration in macrophages.

Colony-stimulating factor 1 (CSF-1) is an important physiological chemoattractant for macrophages. The mechanisms by which CSF-1 elicits the formation of filamentous actin (F-actin)-rich membrane protrusions and induces macrophage migration are not fully understood. In particular, very little is known regarding the contribution of the different members of the Wiskott-Aldrich Syndrome protein (WASP) family of actin regulators in response to CSF-1. Although a role for WASP itself in macrophage chemotaxis has been previously identified, no data was available regarding the function of WASP family verprolin-homologous (WAVE) proteins in this cell type. We found that WAVE2 was the predominant isoform to be expressed in primary macrophages and in cells derived from the murine monocyte/macrophage RAW264.7 cell line (RAW/LR5). CSF-1 treatment of macrophages resulted in WAVE2 accumulation in F-actin-rich protrusions induced by CSF-1. Inhibition of WAVE2 function by expressing a dominant-negative mutant or introducing anti-WAVE2 antibodies in RAW/LR5 cells, as well as reduction of endogenous WAVE2 expression by RNA-mediated interference (RNAi), resulted in a significant reduction of CSF-1-elicited F-actin protrusions. WAVE2 was found in a protein complex together with Abelson kinase interactor 1 (Abi1) in resting or stimulated cells. Both WAVE2 and Abi1 were recruited to and necessary for the formation of F-actin protrusions in response to CSF-1. Reducing the levels of WAVE2, directly or by targeting Abi1, resulted in an impaired cell migration to CSF-1. Altogether these data identify a WAVE2-Abi1 complex crucial for the normal actin cytoskeleton reorganization and migration of macrophages in response to CSF-1.

Actins↗

PubMed2003

Involvement of Wiskott-Aldrich syndrome protein family verprolin-homologous protein (WAVE) and Rac1 in the phagocytosis of amyloid-beta(1-42) in rat microglia.

Alzheimer's disease (AD) is characterized by the accumulation of extracellular amyloid-beta (A beta) fibrils with microglia. Recently, there has been great interest in the microglial phagocytosis of A beta, because the microglial pathway is considered to be one of the A beta clearance pathways in the brain parenchyma. However, the mechanism of microglial phagocytosis of A beta is not fully understood and, thus, was investigated in this study. At one minute after exposure to A beta(1-42) (A beta 42), A beta immunoreactivity was detected at the cell surface of microglia. After 1 h, marked immunoreactivity was observed in the cytosolic vesicles. At 12 h, delayed phagocytosis of fibrillar A beta 42 was also observed with the formation of a large phagocytic cup. The microglial cell shape rapidly changed to an ameboid form during the process of phagocytosis. Although neither neural Wiskott-Aldrich syndrome protein (N-WASP) nor WASP interacting SH3 protein (WISH) immunoreactivity was co-localized with filamentous actin (F-actin) distribution, both WASP family verprolin-homologous protein (WAVE) and Rac1 immunoreactivity was co-localized with F-actin in the lamellipodia of phogocytic microglia. These results suggest that WAVE and Rac1 participate in the phagocytosis of A beta 42 by microglia.

Amyloid beta-Peptides↗

PubMed2004

Genetic analysis of contributions of dorsal group and JAK-Stat92E pathway genes to larval hemocyte concentration and the egg encapsulation response in Drosophila.

Drosophila larvae defend themselves against parasitoid wasps by completely surrounding the egg with layers of specialized hemocytes called lamellocytes. Similar capsules of lamellocytes, called melanotic capsules, are also formed around "self" tissues in larvae carrying gain-of-function mutations in Toll and hopscotch. Constitutive differentiation of lamellocytes in larvae carrying these mutations is accompanied by high concentrations of plasmatocytes, the major hemocyte class in uninfected control larvae. The relative contributions of hemocyte concentration vs. lamellocyte differentiation to wasp egg encapsulation are not known. To address this question, we used Leptopilina boulardi to infect more than a dozen strains of host larvae harboring a wide range of hemocyte densities. We report a significant correlation between hemocyte concentration and encapsulation capacity among wild-type larvae and larvae heterozygous for mutations in the Hopscotch-Stat92E and Toll-Dorsal pathways. Larvae carrying loss-of-function mutations in Hopscotch, Stat92E, or dorsal group genes exhibit significant reduction in encapsulation capacity. Larvae carrying loss-of-function mutations in dorsal group genes (including Toll and tube) have reduced hemocyte concentrations, whereas larvae deficient in Hopscotch-Stat92E signaling do not. Surprisingly, unlike hopscotch mutants, Toll and tube mutants are not compromised in their ability to generate lamellocytes. Our results suggest that circulating hemocyte concentration and lamellocyte differentiation constitute two distinct physiological requirements of wasp egg encapsulation and Toll and Hopscotch proteins serve distinct roles in this process.

Animals↗

PubMed2000

Impact of whole-canopy and systemic insecticidal treatments on Callirhytis cornigera (Hymenoptera: Cynipidae) and associated parasitoids on pin oak.

The gall wasp Callirhytis cornigera (Osten Sacken) is a cynipid with alternating generations that produce large, woody stem galls and tiny blister-like leaf galls on pin oak, Quercus palustris Muenchhausen, in the United States. We tested 3 approaches to control the leaf-galling generation, and determined their impact on associated parasitoids and effectiveness in reducing numbers of new stem galls. First, trees were sprayed with bifenthrin or chlorpyrifos in late March to kill females emerging from stem galls before they oviposited into buds. Second, concentrated solutions of abamectin, imidacloprid, or bidrin were injected from pressurized containers into tree sapwood to control larvae developing in young leaf galls. Finally, systemic insecticides (acephate, abamectin, dimethoate, or imidacloprid) were sprayed at early leaf expansion (2 May) or to young, expanded leaves (17 May) to target larvae in leaf galls. Parasitoids, mostly eulophids, accounted for approximately 70% mortality of leaf-galling C. cornigera larvae on untreated trees. Whole-canopy sprays during C. cornigera emergence from stem galls reduced overall numbers of galled leaves and leaf galls. Trunk injections of bidrin or abamectin resulted in significant mortality of gall inhabitants, including parasitoids. However, neither of the aforementioned approaches significantly reduced numbers of new stem galls. Sprays of abamectin, dimethoate, or imidacloprid applied on 2 May caused high mortality of all gall inhabitants. There was no net benefit, however, because parasitism caused a similar reduction in C. cornigera survival on unsprayed shoots. Sprays applied later in leaf expansion had little impact on gall inhabitants. Of the treatments tested, bifenthrin sprays at bud break provided the greatest reduction in new leaf galls, whereas bidrin injections provided the greatest reduction in gall wasps emerging from galled leaves. This study suggests that gall wasp outbreaks are unlikely to be controlled by a single treatment, regardless of application method.

Animals↗

PubMed2006

Defective Th1 cytokine gene transcription in CD4+ and CD8+ T cells from Wiskott-Aldrich syndrome patients.

Wiskott-Aldrich syndrome (WAS) protein (WASP) plays a key role in TCR-mediated activation and immunological synapse formation. However, the effects of WASP deficiency on effector functions of human CD4+ and CD8+ T cells remain to be determined. In this study, we report that TCR/CD28-driven proliferation and secretion of IL-2, IFN-gamma, and TNF-alpha are strongly reduced in CD8+ T cells from WAS patients, compared with healthy donor CD8+ T cells. Furthermore, WAS CD4+ T cells secrete low levels of IL-2 and fail to produce IFN-gamma and TNF-alpha, while the production of IL-4, IL-5, and IL-10 is only minimally affected. Defective IL-2 and IFN-gamma production persists after culture of naive WAS CD4+ T cells in Th1-polarizing conditions. The defect in Th1 cytokine production by WAS CD4+ and CD8+ T cells is also present at the transcriptional level, as shown by reduced IL-2 and IFN-gamma mRNA transcripts after TCR/CD28 triggering. The reduced transcription of Th1 cytokine genes in WAS CD4+ T cells is associated with a defective induction of T-bet mRNA and a reduction in the early nuclear recruitment of NFAT-1, while the defective activation of WAS CD8+ T cells correlates with reduced nuclear recruitment of both NFAT-1 and NFAT-2. Together, our data indicate that WASP regulates the transcriptional activation of T cells and is required specifically for Th1 cytokine production.

Adult↗

PubMed2000

Wiskott-Aldrich syndrome protein is necessary for efficient IgG-mediated phagocytosis.

Interactions between the Wiskott-Aldrich (WAS) protein (WASp), small GTPases, and the cytoskeletal organizing complex Arp2/3 appear to be critical for the transduction of signals from the cell membrane to the actin cytoskeleton in hematopoietic cells. This study shows that Fcgamma-receptor (FcgammaR)-mediated phagocytosis is impaired in WASp-deficient peripheral blood monocytes, and that in macrophages, formation of the actin cup and local recruitment of tyrosine phosphorylated proteins is markedly attenuated. Results also show that, in normal macrophages, WASp itself is actively recruited to the cup, suggesting that assembly of this specialized cytoskeletal structure is dependent on its expression. (Blood. 2000;95:2943-2946)

Actins↗

PubMed2000

Cellular signaling in macrophage migration and chemotaxis.

Whereas most cells in adult tissues are fixed in place by cell junctions, leukocytes are motile and able to migrate actively through the walls of blood vessels into surrounding tissues. The actin cytoskeleton of these cells plays a central role in locomotion, phagocytosis, and the regulation of cell shape that are crucial elements of neutrophil and monocyte/macrophage function. This review will concentrate on how macrophages in particular control the actin cytoskeleton to generate cell movement and the shape changes required for chemotaxis. It has recently become evident that a complex of seven proteins known as the Arp2/3 complex regulates the assembly of new actin filament networks at the leading front of moving cells. Proteins of the Wiskott-Aldrich Syndrome Protein (WASP) family bind directly to the Arp2/3 complex and stimulate its ability to promote the nucleation of new actin filaments. Upstream of the WASP family proteins, receptor tyrosine kinases, G-protein-coupled receptors, phosphoinositide-3-OH kinase (PI 3-kinase), and the Rho family of GTPases receive and transduce the signals that lead to actin nucleation through WASP-Arp2/3 action. Although many gaps remain in our understanding, we are now in a position to consider completing signaling pathways that are initiated from outside the cell to the actin rearrangements that drive cell motility and chemotaxis.

Animals↗

PubMed2000

Molecular biology of the Wiskott-Aldrich syndrome.

The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency associated with thrombocytopenia, bloody diarrhea, eczema, recurrent infections, and a high incidence of malignancies. X-linked thrombocytopenia (XLT) is a milder form with predominant platelet abnormalities. Both are caused by mutations of the cytoplasmic WAS protein (WASP). To date, mutations of WASP have been identified in over 340 families and consist of missense and nonsense mutations, deletions and insertions, and splice site mutations. There is a striking correlation between phenotype and genotype. The complex gene product of WASP has multiple functional domains that contribute to actin polymerization, cell motility, intracellular signaling, and apoptosis. Understanding the molecular basis of WAS/XLT not only explains the highly variable clinical phenotype, but also affects the medical management of this serious congenital disorder.

Humans↗

PubMed2001

Self-pollination and its costs in a monoecious fig (Ficus aurea, Moraceae) in a highly seasonal subtropical environment.

The unusual floral phenology of most monoecious figs, related to their highly specialized pollination mutualism with agaonid wasps, combines pronounced dichogamy at the level of inflorescences and individuals with population-level asynchrony in flowering. This floral phenology ensures that outcrossing strongly predominates. Fig populations may thus be expected to possess deleterious recessive alleles that lead to inbreeding depression when selfing does occur. However, whether monoecious figs are self-compatible and whether selfing results in inbreeding depression have never been investigated. Using wasps as "pollination tools" and exploiting infrequent overlap in male and female phases on the same tree, we conducted controlled selfed and outcrossed pollination experiments in Ficus aurea. Our results show that this species is totally self-compatible. No negative effects of selfing could be demonstrated on syconium retention, number of vacant ovaries, seed set, or seed germination. However, wasp production had a tendency to be higher after self-pollination. While it is possible that inbreeding depression is expressed at later developmental stages, its absence at the early stages we examined is nonetheless surprising for a plant expected to be highly outcrossed. It is likely that selection pressures other than avoidance of inbreeding are responsible for the evolution and maintenance of the unusual floral phenology of figs.

Journal Article↗

PubMed2003

Efficacy and safety of rush immunotherapy in patients with Hymenoptera allergy in Japan.

In Japan, approximately 40 persons die annually from anaphylaxis caused by Hymenoptera stings. Venom immunotherapy is considered safe and effective for the treatment of allergic systemic reactions caused by Hymenoptera stings in patients with Hymenoptera allergy. We studied the efficacy and safety of rush immunotherapy in patients who had a history of systemic reactions to Hymenoptera stings in Japan. Between 1988 and 2002, 95 patients with a history of systemic reactions to Hymenoptera stings were investigated. The stings originated from honeybees in 5 patients, yellow jackets in 28, wasps in 48, both yellow jackets and wasps in 9, and both yellow jackets and honeybees in 5. All patients had venom-specific IgE antibodies in sera (RAST score > or = 2) and received rush immunotherapy with venom extracts at our hospital. Forty-three patients had 63 field re-stings during immunotherapy. Of these patients, 41 (95.3%) with 59 field re-stings (93.7%) had no systemic reactions. Two patients (4.7%) with four field restings (6.3%) had anaphylactic shock. Although anaphylactic reactions developed in two patients (2.1%) during rush immunotherapy with honeybee venom and one patient (1.1%) during maintenance therapy wasp venom, systemic adverse reactions were mitigated by treatment with antihistamines before venom injection. Our results show that immunotherapy is safe and effective for the prevention of systemic reactions to Hymenoptera re-stings in patients with Hymenoptera allergy. We therefore recommend that patients who are allergic to Hymenoptera venom prophylactically receive immunotherapy.

Adolescent↗