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PubMed1998

Understanding the molecular basis of Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder associated with lymphocytes and platelet abnormalities. The gene that encodes the Wiskott-Aldrich protein (WASP) was recently isolated, and shown to be defective in WAS patients. WASP contains multiple domains that interact with various signalling proteins, including the guanine triphosphatase (GTPase) Cdc42Hs and SH3 domain-containing proteins. Biochemical and genetic evidence strongly suggests that WASP is an important protein in the regulation of cell morphology. Recent progress in the identification of molecular partners for WASP suggests a molecular mechanism for the cellular abnormalities of WAS.

Humans↗

PubMed1995

Polydnaviruses: potent mediators of host insect immune dysfunction.

Endoparasitic insects are used as biological control agents to kill many species of insect pest. One key to the success of parasitoids that develop in the hemocoel of their host is their ability to knock out the host's immune system, inducing a decline in the responsiveness of a variety of cellular and humoral components so that parasitoid eggs are not encapsulated. In many species parasitized by braconid and ichneumonid wasps, host immunosuppression appears to be mediated by polydnaviruses (PDVs) injected by the female parasitoid into the host hemocoel. The viruses exhibit a complex and intimate genetic relationship with the wasp, since viral sequences are integrated within the wasp's chromosomal DNA. Here Mark Lavine and Nancy Beckage summarize the current evidence for mechanisms of virally induced host immunosuppression in parasitized insects, as well as the roles of other factors including wasp ovarian proteins and venom components, in suppressing hemocyte-mediated and humoral immune responses. Interestingly, in some species, the PDV-induced host immunosuppression appears transitory, with older parasitoid larvae probably exploiting other mechanisms to protect themselves from the host's immune system during the final stages of parasitism. During the final stages of parasitism, the parasitoids likely exploit other mechanisms of immunoevasion via antigen masking, antigen mimicry, or production of active inhibitors of the hemocyte-mediated encapsulation response as well as inhibiting melanization.

Journal Article↗

PubMed2005

Adaptive value of host discrimination in parasitoids: when host defences are very costly.

Host acceptance decision in parasitic wasps strongly depends on the parasitism status of the encountered host. In solitary species, a host only allows the development of a single parasitic larva and then, any oviposition in an already parasitised host leads to larval competition and loss of offspring. Females of many parasitoid species are able to discriminate between parasitised hosts and healthy ones. However, the host discrimination process may require more time than oviposition, exposing the wasp to high risks when the host has efficient defences. Consequently, depending on the degree of success of the host defence, the cost of host inspection for discrimination can outweigh the benefit of superparasitism avoidance. In the present paper, a theoretical approach was developed for determining how host defences may affect optimal host acceptance behaviour in parasitoids. The present model compares the lifetime reproductive success over the strategy used, discrimination and no-discrimination: a discriminating wasp sets a relatively greater value in its current oviposition, while a non-discriminating female sets a greater value in its own survival and future reproduction. The model predicts that depending on physiological state variables and environmental state variables, the optimal policy is not discriminating. Our results suggest that the low discriminating ability observed in some parasitic wasps could probably be an evolutionary response to host defences pressure.

Adaptation, Physiological↗

PubMed2005

WIP: a multifunctional protein involved in actin cytoskeleton regulation.

Knowledge of the dynamics of actin-based structures is a major key to understanding how cells move and respond to their environment. The ability to reorganize actin filaments in a spatial and temporal manner to integrate extracellular signals is at the core of cell adhesion and cell migration. Several proteins have been described as regulators of actin polymerization: this review will focus on the role of WASP-interacting protein (WIP), an actin-binding protein that participates in actin polymerization regulation and signal transduction. WIP is widely expressed and interacts with Wiskott-Aldrich syndrome protein (WASP) (a hematopoietic-specific protein) and its more widely expressed homologue neural WASP (N-WASP), to regulate WASP/N-WASP function in Arp2/3-mediated actin polymerization. WIP also interacts with profilin, globular and filamentous actin (G- and F-actin, respectively) and stabilizes actin filaments. In vivo WIP participates in filopodia and lamellipodia formation, in T and B lymphocyte activation, in mast cell degranulation and signaling through the Fcepsilon receptor (FcepsilonR), in microbial motility and in Syk protein stability.

Actin Cytoskeleton↗

PubMed2005

Defective nuclear translocation of nuclear factor of activated T cells and extracellular signal-regulated kinase underlies deficient IL-2 gene expression in Wiskott-Aldrich syndrome.

BACKGROUND: Proliferation and IL-2 production in response to T-cell receptor ligation are impaired in patients with Wiskott-Aldrich syndrome (WAS). The transcription factors nuclear factor-kappaB (NF-kappaB), nuclear factor of activated T cells (NF-AT), and activating protein-1 (AP-1) play a critical role in IL-2 gene expression. OBJECTIVE: To investigate the mechanisms of impaired IL-2 production after T-cell receptor ligation in T cells deficient in WAS protein (WASP). METHODS: T cells from WASP-/- mice were stimulated with anti-CD3 and anti-CD28. Nuclear NF-kappaB, NF-AT, and AP-1 DNA-binding activity was examined by electroshift mobility assay. NF-ATp dephosphorylation and nuclear localization were examined by Western blot and indirect immunofluorescence. Phosphorylation of the mitogen-activated protein kinases Erk and Jnk, and of their nuclear substrates Elk-1 and c-Jun, was examined by Western blot. Expression of mRNA for IL-2 and the NF-kappaB-dependent gene A20 and of the AP-1 components c-fos and c-Jun was examined by quantitative RT-PCR. RESULTS: Nuclear translocation and activity of NF-kappaB were normal in T cells from WASP-/- mice. In contrast, NF-ATp dephosphorylation and nuclear localization, nuclear AP-1 binding activity, and expression of c-fos, but not c-Jun, were all impaired. Phosphorylation of Jnk, c-Jun, and Erk were normal. However, nuclear translocation of phosphorylated Erk and phosphorylation of its nuclear substrate Elk1, which activates the c-fos promoter, were impaired. CONCLUSION: These results suggest that WASP is essential for NF-ATp activation, and for nuclear translocation of p-Erk, Elk1 phosphorylation, and c-fos gene expression in T cells. These defects underlie defective IL-2 expression and T-cell proliferation in WAS.

Active Transport, Cell Nucleus↗

PubMed2004

Wall-less sample preparation of microm-sized sample spots for femtomole detection limits of proteins from liquid based UV-MALDI matrices.

Previously, we introduced wall-less sample preparation (WaSP), technology that involves the use of an electrodynamic balance (EDB) to prepare microm-sized sample spots for analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). In that work we demonstrated the detection of femtomole quantities of a low molecular weight peptide and a hydrophobic ester (both <600 Da). Here we use WaSP to test the hypothesis that the use of small sample spot sizes and an instrument equipped with delayed extraction would increase the analytical utility of liquid sample spots for peptide and protein (>2500 Da) analysis by UV-MALDI-TOF-MS (Sze et al.; J. Am. Soc. Mass Spectrom. 1998, 9, 166-174). To aid the optimization of preparing microm-sized sample spots by WaSP, optical microscopy and mass spectrometry were used to investigate nonvolatile solute concentration effects on droplet fission and sample spot size, modifications of the EDB electric field to control droplet ejection, and the use of multiple droplet deposition to increase sample loading. Also described is a rapid deposition mode of operation for WaSP that allows single droplets generated at 1 Hz to be levitated briefly ( approximately 500 ms) before being ejected autonomously and deposited as a concentrated sample spot with a spatial accuracy of +/-5 microm. To test the sensitivity of the method, one hundred glycerol droplets (270 pL each, 27 nL total) each containing 32 amol lysozyme were deposited on top of each other one-at-a-time to create a single sample spot. Using a mass spectrometer equipped with delayed extraction to analyze this sample spot, we verified the hypothesis of Sze et al. by achieving detection limits three orders of magnitude below that previously observed for the detection of a protein by UV-MALDI-TOF-MS with a chemical-doped liquid matrix sample preparation.

Adrenocorticotropic Hormone↗

PubMed2006

Cortactin binding to F-actin revealed by electron microscopy and 3D reconstruction.

Cortactin and WASP activate Arp2/3-mediated actin filament nucleation and branching. However, different mechanisms underlie activation by the two proteins, which rely on distinct actin-binding modules and modes of binding to actin filaments. It is generally thought that cortactin binds to "mother" actin filaments, while WASP donates actin monomers to Arp2/3-generated "daughter" filament branches. Interestingly, cortactin also binds WASP in addition to F-actin and the Arp2/3 complex. However, the structural basis for the role of cortactin in filament branching remains unknown, making interpretation difficult. Here, electron microscopy and 3D reconstruction were carried out on F-actin decorated with the actin-binding repeating domain of cortactin, revealing conspicuous density on F-actin attributable to cortactin that is located on a consensus-binding site on subdomain-1 of actin subunits. Strikingly, the binding of cortactin widens the gap between the two long-pitch filament strands. Although other proteins have been found to alter the structure of the filament, the cortactin-induced conformational change appears unique. The results are consistent with a mechanism whereby alterations of the F-actin structure may facilitate recruitment of the Arp2/3 complex to the "mother" filament in the cortex of cells. In addition, cortactin may act as a structural adapter protein, stabilizing nascent filament branches while mediating the simultaneous recruitment of Arp2/3 and WASP.

Actin-Related Protein 2↗

PubMed2006

The structural basis of actin interaction with multiple WH2/beta-thymosin motif-containing proteins.

Participation of actin in cellular processes relies on the dynamics of filament assembly. Filament elongation is fed by monomeric actin in complex with either profilin or a Wiscott-Aldrich syndrome protein (WASP) homology domain 2 (WH2)/beta-thymosin (betaT) domain. WH2/betaT motif repetition (typified by ciboulot) or combination with nonrelated domains (as found in N-WASP) results in proteins that yield their actin to filament elongation. Here, we report the crystal structures of actin bound hybrid proteins, constructed between gelsolin and WH2/betaT domains from ciboulot or N-WASP. We observe the C-terminal half of ciboulot domain 2 bound to actin. In solution, we show that cibolout domains 2 and 3 bind to both G- and F-actin, and that whole ciboulot forms a complex with two actin monomers. In contrast, the analogous portion of N-WASP WH2 domain 2 is detached from actin, indicating that the C-terminal halves of the betaT and WH2 motifs are not functionally analogous.

Actins↗

PubMed2005

Modulation of nicotinic acetylcholine and N-methyl-d-aspartate receptors by some Hymenopteran venoms.

The effect of 19 venoms from solitary wasps, solitary bees, social wasps and ants were investigated for their effects on nicotinic acetylcholine receptors (nAChR) and ionotropic glutamate receptors (IGRs) of both the N-methyl-d-aspartate (NMDAR) and non-NMDAR type. Whole-cell patch clamp of human muscle TE671 cells was used to study nAChR, and of rat cortical and cerebellar granule cells for IGRs. Solitary wasp venoms caused significant voltage-dependent antagonism of nAChR responses to 10 microM ACh and NMDAR responses to 100 microM NMDA (+10 microM glycine) when co-applied at 1 microg/ml with the agonists. At positive holding potentials (V(H)) potentiation of these receptors was observed with some venoms. Solitary bee venoms only affected nAChR by causing either voltage-independent antagonism or potentiation of their responses to 10 microM ACh. Of four social wasp venoms, one acted on nAChR by potentiating responses to 10 ACh, while another generated an ACh-like response when applied alone. They had no effect on IGRs. Of the two ant venoms, one caused voltage-independent inhibition of nAChR. Neither affected IGRs. The data indicate the presence of nAChR agonists and antagonists and NMDAR antagonists in Hymenopteran venoms and warrant further investigation to separate and identify these venom components.

Animals↗

PubMed2004

Lentiviral vector-mediated gene transfer in T cells from Wiskott-Aldrich syndrome patients leads to functional correction.

Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency with a median survival below the age of 20 due to infections, severe hemorrhage, and lymphomas. Transplantation of hematopoietic stem cells from HLA-identical sibling donors is a resolutive treatment, but is available for a minority of patients. Transplantation of genetically corrected autologous hematopoietic stem cells or T cells could represent an alternative treatment applicable to all patients. We investigated whether WAS gene transfer with MMLV-based oncoretroviral and HIV-based lentiviral vectors could restore normal functions of patients' T cells. T cells transduced either with lentiviral vectors expressing the WAS protein (WASP) from the ubiquitous PGK promoter or the tissue-specific WASP promoter or with an oncoretroviral vector expressing WASP from the LTR, reached normal levels of WASP with correction of functional defects, including proliferation, IL-2 production, and lipid raft upregulation. Lentiviral vectors transduced T cells from WAS patients at higher rates, compared to oncoretroviral vectors, and efficiently transduced both activated and naive WAS T cells. Furthermore, a selective growth advantage of T cells corrected with the lentiviral vectors was demonstrated. The observation that lentiviral vector-mediated gene transfer results in correction of T cell defects in vitro supports their application for gene therapy in WAS patients.

Antibodies↗

PubMed2002

WH2 domain: a small, versatile adapter for actin monomers.

The actin cytoskeleton plays a central role in many cell biological processes. The structure and dynamics of the actin cytoskeleton are regulated by numerous actin-binding proteins that usually contain one of the few known actin-binding motifs. WH2 domain (WASP homology domain-2) is a approximately 35 residue actin monomer-binding motif, that is found in many different regulators of the actin cytoskeleton, including the beta-thymosins, ciboulot, WASP (Wiskott Aldrich syndrome protein), verprolin/WIP (WASP-interacting protein), Srv2/CAP (adenylyl cyclase-associated protein) and several uncharacterized proteins. The most highly conserved residues in the WH2 domain are important in beta-thymosin's interactions with actin monomers, suggesting that all WH2 domains may interact with actin monomers through similar interfaces. Our sequence database searches did not reveal any WH2 domain-containing proteins in plants. However, we found three classes of these proteins: WASP, Srv2/CAP and verprolin/WIP in yeast and animals. This suggests that the WH2 domain is an ancient actin monomer-binding motif that existed before the divergence of fungal and animal lineages.

Actins↗

PubMed2001

Nestmate recognition in Parischnogaster striatula (Hymenoptera Stenogastrinae), visual and olfactory recognition cues.

The recognition of nestmates from alien individuals is a well known phenomenon in social insects. In the stenogastrine wasp Parischnogaster striatula, we investigated the ability of females to recognize nestmates and the cues on which such recognition is based. Recognition of nestmates was observed in naturally occurring interactions between wasps approaching a nest and the resident females on that nest. This recognition was confirmed in experiments in which nestmates or alien conspecifics were presented to resident females. In naturally occurring interactions, nestmates generally approach their nest with a direct flight, while aliens usually hover in front of the nest before landing. In experiments in which the presented wasps were placed close to the nest in a direct manner, antennation of the presented wasp generally occurred, indicating that chemical cues are involved. Experiments in which dead alien individuals, previously washed in hexane, and then reapplied with extracts were recognized by colonies giving further evidence that chemical cues mediate nestmate recognition. Epicuticular lipids, known to be nestmate recognition cues in social insects, were chemically analysed by GC-MS for 44 P. striatula females from two different populations (13 different colonies). Discriminant analysis was performed on the data for the lipid mixture composition. The discriminant model showed that, in the samples from these two populations, 68.2% and 81.9% of the specimens could be correctly assigned to their colony.

Journal Article↗

PubMed2002

Effects of the Diadromus pulchellus ascovirus, DpAV-4, on the hemocytic encapsulation response and capsule melanization of the leek-moth pupa, Acrolepiopsis assectella.

DpAV-4 is a symbiotic ascovirus found in natural populations of the solitary endoparasitoid wasp Diadromus pulchellus. The female wasp injects this virus into the pupae of the leek-moth Acrolepiopsis assectella during oviposition. The ascovirus replicates in the pupal tissues and the consequent lysis of the cells occurs synchronously with egg hatching and the development of the wasp larva. We show here that encapsulation and capsule melanization were activated when minute nylon monofilaments were implanted into the hemocoel of non parasitized leek-moth pupae and that encapsulation and melanization were inhibited in pupae parasitized by D. pulchellus. When the pupae were infected by DpAV-4, melanization of the nylon monofilaments was abolished, but a capsule was still always formed. These results indicate that DpAV-4 is a free virus able to alter the defence system of the parasitized host so as to improve the development of the parasitoid wasp, D. pulchellus.

Journal Article↗

PubMed1996

Isolated X-linked thrombocytopenia in two unrelated families is associated with point mutations in the Wiskott-Aldrich syndrome protein gene.

The Wiskott-Aldrich syndrome (WAS) is characterized by defective platelet and lymphocyte function associated with eczema and increased susceptibility to malignancies. It is caused by mutations of the WAS protein-encoding gene (WASP). X-lined thrombocytopenia, defined by low platelet counts and volume, may be an allelic variant of WAS. In patients with XLT from two unrelated families, WASP gene defects were identified by single-strand conformational polymorphism and by sequencing. Point mutations in exon 2 of the WASP gene were found in the patients from both families in which XLT segregated. Several obligate heterozygote female members of these families display a random pattern of X inactivation in their peripheral blood leukocytes. This study shows that XLT may be caused by mutations of the WASP, thus representing an allelic variant of WAS.

Adult↗

PubMed2002

A comparison of rate-response toxicity tests with Aphidius rhopalosiphi (Hymenoptera: Aphidiidae) using glass, leaves and whole plants as substrate.

Rate-response toxicity tests on Aphidius rhopalosiphi were carried out with seven plant protection products using three different test systems. The first type of test system conformed to the standard laboratory testing guidelines and consisted of two treated glass plates fitted into a metal frame, which created an enclosure for the wasps. In the second type of test system, the plant protection products were applied to two bean-leaf disks mounted on agar filled dishes, which were fitted to a transparent plastic frame. The third type of test system consisted of potted barley plants, which were treated and covered with an acrylic cylinder. Adult wasps were exposed to the dried residues of the products for 48 h before wasp mortality was assessed. For each product and test system, the LR50 value (application rate at which 50% mortality of the wasps occurs) was determined with a Bayesian Probit analysis. Technically, rate-response testing was feasible with all three test systems, and rate-response relationships could be established. The results support a sequential testing scheme, as the LR50 values increased from 'glass plate test' to 'excised leaf test' to 'whole plant test' with all tested products. The LR50 values were 7.8-340 times higher on whole plants than on glass plates. Because of the variability of this factor, a numerical safety factor cannot be used to substitute extended laboratory testing for regulatory purposes.

Animals↗

PubMed2003

Wiskott-Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation.

Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune disorders and increased incidence of malignancies. Classic WAS, and a milder form, X-linked thrombocytopenia, are caused by mutations of the WAS protein (WASP) gene. Recent investigations have provided evidence that WASP and several related proteins are involved in the reorganization of the actin cytoskeleton by activating Arp2/3-mediated actin polymerization. This function is controlled by the small GTPase Cdc42, which regulates the autoinhibitory loop formation of WASP. In addition, WASP is involved in cytoplasmic signaling via its interaction with a variety of adaptor molecules. Mutation analysis of large cohorts of WAS/X-linked thrombocytopenia patients has provided evidence for a strong correlation between phenotype and genotype.

Actins↗

PubMed2002

Regulation of Wiskott-Aldrich syndrome protein and related molecules.

Wiskott-Aldrich syndrome protein (WASP), the gene mutated in the haematological disorder Wiskott-Aldrich syndrome, is the founding member of a family of conserved cytoskeletal regulators. WASP family proteins regulate actin dynamics through binding and activation of the Arp2/3 complex, which nucleates new actin filaments. Recently, a huge amount of information on WASPs has become available, both in terms of the function of individual domains, identification of their binding partners, and the unravelling of complex regulatory mechanisms. Together, these new findings place WASP-related molecules at the crossroads between distinct signalling pathways, which they integrate into coherent cytoskeletal responses.

Actin Cytoskeleton↗

PubMed2002

Grb2 and Nck act cooperatively to promote actin-based motility of vaccinia virus.

The Wiskott-Aldrich syndrome protein family member N-WASP is a key integrator of the multiple signalling pathways that regulate actin polymerization via the Arp2/3 complex. Our previous studies have shown that N-WASP is required for the actin-based motility of vaccinia virus and is recruited via Nck and WIP. We now show that Grb2 is an additional component of the vaccinia actin tail-forming complex. Recruitment of Nck and Grb2 to viral particles requires phosphorylation of tyrosine residues 112 and 132 of A36R, the vaccinia actin tail nucleator, respectively. The presence of Grb2 on the virus is also dependent on the polyproline-rich region of N-WASP. The Grb2 pathway alone is therefore unable to nucleate actin tails, as its recruitment requires the prior recruitment of N-WASP by Nck. However, Grb2 does play an important role in actin-based motility of vaccinia, as in its absence, the mean number of actin tails per cell is reduced 2.6-fold. Thus, both Nck and Grb2 act in a cooperative manner to stabilize and/or activate the vaccinia actin-nucleating complex. We suggest that such cooperativity between "primary" and "secondary" adaptor proteins is likely to be a general feature of receptor-mediated signalling.

Actins↗