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PubMed2002

Retrovirus-mediated WASP gene transfer corrects Wiskott-Aldrich syndrome T-cell dysfunction.

The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema, and immunodeficiency. At present, the only definitive therapy for the disease is allogeneic bone marrow transplantation (BMT). Because of the frequent lack of suitable donors and the potential severe complications associated with BMT, the development of gene-based therapeutic strategies for WAS is highly desirable. To study whether corrective gene transfer into WAS T cells can lead to restoration of the immunologic defects of WAS, a retroviral vector expressing the WAS protein (WASP) gene was used to transduce human T-lymphotropic virus type 1-transformed T-cell lines and primary T lymphocytes from patients with WAS. After transduction, WAS T cells showed levels of WASP expression similar to those found in cells from normal individuals. In addition, the reconstituted WASP interacted in vitro with proteins containing SH3 domain such as Grb2, PLC-gamma1, and Fyn, each of which are connected to signaling pathways linked to the actin cytoskeleton. Furthermore, after CD3 cross-linking, transduced WAS T lines showed improvement of actin polymerization and T-cell receptor/CD3 down-regulation. More importantly, primary WAS T lymphocytes transduced with WASP acquired the ability to proliferate in response to anti-CD3 stimulation. These findings suggest that biologic defects of WAS T cells can be corrected in vitro by retrovirus-mediated gene transfer and pose the basis for future investigation of gene therapy as treatment for WAS.

Actins↗
PubMed2006

WASP-interacting protein is important for actin filament elongation and prompt pseudopod formation in response to a dynamic chemoattractant gradient.

The role of WASP-interacting protein (WIP) in the process of F-actin assembly during chemotaxis of Dictyostelium was examined. Mutations of the WH1 domain of WASP led to a reduction in binding to WIPa, a newly identified homolog of mammalian WIP, a reduction of F-actin polymerization at the leading edge, and a reduction in chemotactic efficiency. WIPa localizes to sites of new pseudopod protrusion and colocalizes with WASP at the leading edge. WIPa increases F-actin elongation in vivo and in vitro in a WASP-dependent manner. WIPa translocates to the cortical membrane upon uniform cAMP stimulation in a time course that parallels F-actin polymerization. WIPa-overexpressing cells exhibit multiple microspike formation and defects in chemotactic efficiency due to frequent changes of direction. Reduced expression of WIPa by expressing a hairpin WIPa (hp WIPa) construct resulted in more polarized cells that exhibit a delayed response to a new chemoattractant source due to delayed extension of pseudopod toward the new gradient. These results suggest that WIPa is required for new pseudopod protrusion and prompt reorientation of cells toward a new gradient by initiating localized bursts of actin polymerization and/or elongation.

Actin Cytoskeleton↗
PubMed2000

Signal transduction. N-WASP regulation--the sting in the tail.

Signaling proteins can be regulated by their interactions with other proteins and phospholipids. As Fawcett and Pawson discuss in their Perspective, activation of the N-WASP protein (which coordinates formation of actin filaments) is far more complex, depending on the interaction of N-WASP with both a protein and a phospholipid. The authors explain new results (Prehoda et al.) demonstrating that cooperative binding of the phospholipid PIP2 and the small GTPase Cdc42 to N-WASP results in its activation. The Arp2/3 complex is then able to bind to N-WASP and to proceed with its job of initiating the assembly of actin monomers into actin filaments.

Actin Cytoskeleton↗
PubMed2000

Integration of multiple signals through cooperative regulation of the N-WASP-Arp2/3 complex.

The protein N-WASP [a homolog to the Wiskott-Aldrich syndrome protein (WASP)] regulates actin polymerization by stimulating the actin-nucleating activity of the actin-related protein 2/3 (Arp2/3) complex. N-WASP is tightly regulated by multiple signals: Only costimulation by Cdc42 and phosphatidylinositol (4,5)-bisphosphate (PIP2) yields potent polymerization. We found that regulation requires N-WASP's constitutively active output domain (VCA) and two regulatory domains: a Cdc42-binding domain and a previously undescribed PIP(2)-binding domain. In the absence of stimuli, the regulatory modules together hold the VCA-Arp2/3 complex in an inactive "closed" conformation. In this state, both the Cdc42- and PIP2-binding sites are masked. Binding of either input destabilizes the closed state and enhances binding of the other input. This cooperative activation mechanism shows how combinations of simple binding domains can be used to integrate and amplify coincident signals.

Actin Cytoskeleton↗
PubMed1986

Campoletis sonorensis Endoparasitic Wasps Contain Forms of C. sonorensis Virus DNA Suggestive of Integrated and Extrachromosomal Polydnavirus DNAs.

Campoletis sonorensis virus (CsV) (Polydnaviridae) previously was detected only in the calyx epithelial cells and lumen of the oviducts from female C. sonorensis (Ichneumonidae) endoparasitic wasps (Norton et al., Cell Tissue Res. 162:195-208, 1975). Using dot-blot hybridizations, we detected low amounts of CsV DNA in male and female wasp head and thorax tissues and in male abdominal tissues. Low amounts of extrachromosomal viral DNA were detected in Southern blots of undigested male wasp DNA and in male DNA purified by isopycnic centrifugation. High-molecular-weight male wasp DNA digested with any of several restriction endonucleases and hybridized with cloned viral DNAs from CsV superhelices B and Q under stringent conditions contained CsV-specific DNA fragments that differed significantly in size and number from the hybridizing fragments detected in comparably digested viral DNA. Identical offsize restriction fragments were detected in digested female head and thorax DNA. These data suggest that at least CsV DNAs B and Q are integrated in C. sonorensis cellular DNA and that the virus may be transmitted through the germline.

Journal Article↗
PubMed2005

Abl kinases regulate actin comet tail elongation via an N-WASP-dependent pathway.

Microbial pathogens have evolved diverse strategies to modulate the host cell cytoskeleton to achieve a productive infection and have proven instrumental for unraveling the molecular machinery that regulates actin polymerization. Here we uncover a mechanism for Shigella flexneri-induced actin comet tail elongation that links Abl family kinases to N-WASP-dependent actin polymerization. We show that the Abl kinases are required for Shigella actin comet tail formation, maximal intracellular motility, and cell-to-cell spread. Abl phosphorylates N-WASP, a host cell protein required for actin comet tail formation, and mutation of the Abl phosphorylation sites on N-WASP impairs comet tail elongation. Furthermore, we show that defective comet tail formation in cells lacking Abl kinases is rescued by activated forms of N-WASP. These data demonstrate for the first time that the Abl kinases play a role in the intracellular motility and intercellular dissemination of Shigella and uncover a new role for Abl kinases in the regulation of pathogen motility.

Actins↗
PubMed1999

The Wiskott-Aldrich syndrome protein (WASP): roles in signaling and cytoskeletal organization.

The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked primary immunodeficiency that is characterized by recurrent infections, hematopoietic malignancies, eczema, and thrombocytopenia. A variety of hematopoietic cells are affected by the genetic defect, including lymphocytes, neutrophils, monocytes, and platelets. Early studies noted both signaling and cytoskeletal abnormalities in lymphocytes from WAS patients. Following the identification of WASP, the gene mutated in patients with this syndrome, and the more generally expressed WASP homologue N-WASP, studies have demonstrated that WASP-family molecules associate with numerous signaling molecules known to alter the actin cytoskeleton. WASP/N-WASP may depolymerize actin directly and/or serve as an adaptor or scaffold for these signaling molecules in a complex cascade that regulates the cytoskeleton.

Animals↗
PubMed2001

Comparison of brain volumes between single and multiple foundresses in the paper wasp Polistes dominulus.

Queens of the paper wasp Polistes dominulus have the option to found nests in spring alone or together with other queens. In the latter case a dominance hierarchy is established among the cofoundresses with the dominant wasp getting the major share of the reproductive output of the nest. The different reproductive strategies of an individual wasp will necessitate different behaviors. We measured the volumes of brain structures as a potential indicator of differential use and elaboration of a number of brain structures. We found a significant increase in the volume of the antennal lobe in members of multiple foundress associations in comparison to single foundresses. The volume of the collar, a substructure of the calyx of the mushroom body, was also significantly larger, especially in the dominant queen of a foundress association. No significant differences between dominant or subordinate wasps in regard to volume of the measured brain substructures were found.

Animals↗
PubMed2004

Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. X-linked thrombocytopenia (XLT) is an allelic variant of WAS which presents with a milder phenotype, generally limited to thrombocytopenia. WAS and XLT are caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene which encodes a 502-amino acid protein, named WASP. WASP is thought to play a role in actin cytoskeleton organization and cell signaling. Here, we report the identification of 141 unique mutations, 71 not previously reported, from 227 WAS/XLT families with a total of 262 affected members. When possible we studied the effects of these mutations on transcription, RNA splicing, and protein expression. By analyzing a large number of patients with WAS/XLT at the molecular level we identified 5 mutational hotspots in the WASP gene and have been able to establish a strong association between genotype and phenotype.

Child↗
PubMed2005

WASP-related proteins, Abi1 and Ena/VASP are required for Listeria invasion induced by the Met receptor.

Internalisation of the pathogenic bacterium Listeria monocytogenes involves interactions between the invasion protein InlB and the hepatocyte growth factor receptor, Met. Using colocalisation studies, dominant-negative constructs and small interfering RNA (siRNA), we demonstrate a cell-type-dependent requirement for various WASP-related proteins in Listeria entry and InlB-induced membrane ruffling. The WAVE2 isoform is essential for InlB-induced cytoskeletal rearrangements in Vero cells. In HeLa cells, WAVE1, WAVE2 and N-WASP cooperate to promote these processes. Abi1, a key component of WAVE complexes, is recruited at the entry site in both cell types and its inactivation by RNA interference impairs InlB-mediated processes. Ena/VASP proteins also play a role in Listeria internalization, and their deregulation by sequestration or overexpression, modifies actin cups beneath entering particles. Taken together, these results identify the WAVE complex, N-WASP and Ena/VASP as key effectors of the Met signalling pathway and of Listeria entry and highlight the existence of redundant and/or cooperative functions among WASP-family members.

Adaptor Proteins, Signal Transducing↗
PubMed2002

N-WASP activation by a beta1-integrin-dependent mechanism supports PI3K-independent chemotaxis stimulated by urokinase-type plasminogen activator.

Urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR) and epidermal growth factor (EGF)-EGF receptor (EGFR) expression is highly correlated with breast cancer metastasis. Phosphoinositide 3-kinase (PI3K), small Rho GTPases, such as Cdc42 and Rac1, and neuronal Wiskott Aldrich syndrome protein (N-WASP) are key effectors that regulate dynamic changes in the actin cytoskeleton and cell migration. uPA- and EGF-stimulated chemotaxis, cytoskeletal rearrangements and activation of Cdc42, Rac1 and N-WASP were studied in the highly metastatic human breast cancer cell line MDA MB 231. These studies reveal that divergent signalling occurs downstream of PI3K. The activity of PI3K was not necessary for uPA-induced chemotactic responses, but those induced by EGF were entirely dependent upon PI3K. Furthermore, PI3K-independent chemotactic signalling by uPA was shown to involve disruption of an interaction between beta(1)-integrins and N-WASP and translocation of N-WASP to the actin cytoskeleton.

Actins↗
PubMed2004

Caenorhabditis elegans WASP and Ena/VASP proteins play compensatory roles in morphogenesis and neuronal cell migration.

We report here that WASP and Ena/VASP family proteins play overlapping roles in C. elegans morphogenesis and neuronal cell migration. Specifically, these studies demonstrate that UNC-34/Ena plays a role in morphogenesis that is revealed only in the absence of WSP-1 function and that WSP-1 has a role in neuronal cell migration that is revealed only in the absence of UNC-34/Ena activity. To identify additional genes that act in parallel to unc-34/ena during morphogenesis, we performed a screen for synthetic lethals in an unc-34 null mutant background utilizing an RNAi feeding approach. To our knowledge, this is the first reported RNAi-based screen for genetic interactors. As a result of this screen, we identified a second C. elegans WASP family protein, wve-1, that is most homologous to SCAR/WAVE proteins. Animals with impaired wve-1 function display defects in gastrulation, fail to undergo proper morphogenesis, and exhibit defects in neuronal cell migrations and axon outgrowth. Reducing wve-1 levels in either unc-34/ena or wsp-1 mutant backgrounds also leads to a significant enhancement of the gastrulation and morphogenesis defects. Thus, unc-34/ena, wsp-1, and wve-1 play overlapping roles during embryogenesis and unc-34/ena and wsp-1 play overlapping roles in neuronal cell migration. These observations show that WASP and Ena/VASP proteins can compensate for each other in vivo and provide the first demonstration of a role for Ena/VASP proteins in gastrulation and morphogenesis. In addition, our results provide the first example of an in vivo role for WASP family proteins in neuronal cell migrations and cytokinesis in metazoans.

Animals↗
PubMed1999

Mass envenomations by honey bees and wasps.

Stinging events involving honey bees and wasps are rare; most deaths or clinically important incidents involve very few stings (< 10) and anaphylactic shock. However, mass stinging events can prove life-threatening via the toxic action of the venom when injected in large amounts. With the advent of the Africanized honey bee in the southwestern United States and its potential for further spread, mass envenomation incidents will increase. Here we review the literature on mass stinging events involving honey bees and wasps (i.e., yellowjackets, wasps, and hornets). Despite different venom composition in the two insect groups, both may cause systemic damage and involve hemolysis, rhabdomyolysis, and acute renal failure. Victim death may occur due to renal failure or cardiac complications. With supportive care, however, most victims should be able to survive attacks from hundreds of wasps or approximately 1000 honey bees.

Anaphylaxis↗
PubMed2005

Parasitoid wasp uses a venom cocktail injected into the brain to manipulate the behavior and metabolism of its cockroach prey.

Unlike other venomous predators, the parasitoid wasp Ampulex compressa incapacitates its prey, the cockroach Periplaneta americana, to provide a fresh food supply for its offspring. We first established that the wasp larval development, from egg laying to pupation, lasts about 8 days during which the cockroach must remain alive but immobile. To this end, the wasp injects a cocktail of neurotoxins to manipulate the behavior of the cockroach. The cocktail is injected directly into the head ganglia using biosensors located on the stinger. The head sting induces first 30 min of intense grooming followed by hypokinesia during which the cockroach is unable to generate an escape response. In addition, stung cockroaches survive longer, lose less water, and consume less oxygen. Dopamine contained in the venom appears to be responsible for inducing grooming behavior. For the hypokinesia, our hypothesis is that the injected venom affects neurons located in the head ganglia, which send descending tonic input to bioaminergic neurons. These, in turn, control the thoracic premotor circuitry for locomotion. We show that the activity of identified octopaminergic neurons from the thoracic ganglia is altered in stung animals. The alteration in the octopaminergic neurons' activity could be one of the mechanisms by which the venom modulates the escape circuit in the cockroach's central nervous system and metabolism in the peripheral system.

Animals↗
PubMed2006

In vivo and in vitro activity of venom from the endoparasitic wasp Pimpla turionellae (L.) (Hymenoptera: Ichneumonidae).

The biological activity of venom from Pimpla turionellae L. (Hymenoptera: Ichneumonidae) was examined in vivo toward larvae and pupae of Galleriae mellonella L. (Lepidoptera: Pyralidae), and in vitro toward bacterial and fungal cultures, as well as cultured insect cells. Pupae of G. mellonella were far more susceptible to the venom than larvae. At low doses of venom [0.1 venom reservoir equivalents (VRE)], pupal abdominal mobility was inhibited within 30 min, and by 24 h, all pupae injected with venom concentrations >0.5 VRE were completely paralyzed. These same doses of venom resulted in an inhibition of adult emergence. Host larvae were far less sensitive to wasp venom as evidenced by all venom injected larvae remaining responsive to mechanical stimulation by 1 h post injection, even at concentrations equivalent to 1 venom reservoir. Eventually (>2 h at 25 degrees C), venom-injected larvae became immobile, then flaccid, and all died within 24 h post-injection. At lower concentrations of wasp venom, the onset of paralysis was delayed by comparison to that evoked by 1 VRE, and few host larvae were able to pupate. Development of host larvae to adult emergence was also reduced in a dose-dependent manner, with eclosion completely prevented at high concentrations (>0.5 VRE) of venom. Venom doses <0.5 VRE did not appear to induce paralysis or alter larval development. When venom was incubated with bacterial or fungal cultures, no antimicrobial activity was detected. However, wasp venom was found to be cytotoxic and cytolytic to cultured cells derived from the cabbage looper Trichoplusia ni Hubner (Lepidoptera: Noctuidae) and the yellow fever mosquito, Aedes aegypti (L.) (Diptera: Culcidae). Though both cell types displayed similar susceptibility in terms of LC50s, the lepidopteran cells responded much more rapidly with regard to the onset of morphological changes and the timing of cell death. A possible mode of action for the venom is discussed.

Animals↗
PubMed2003

Wasp venom blocks central cholinergic synapses to induce transient paralysis in cockroach prey.

The parasitoid wasp Ampulex compressa induces a set of unique behavioral effects upon stinging its prey, the cockroach. It stings into the first thoracic segment inducing 2 to 3 min of transient flaccid paralysis of the front legs. This facilitates a second sting in the cockroach's head that induces 30 min of excessive grooming followed by a 2 to 5-week long lethargic state. In the present study, we examine the immediate effect of the first sting, which is a transient paralysis of the front legs. Using radiolabeled wasps, we demonstrate that the wasp injects its venom directly into the cockroach's first thoracic ganglion. The artificial injection of milked venom into a thoracic ganglion abolishes spontaneous and evoked responses of the motoneurons associated with leg movements. To investigate the physiological mechanism of action of the venom, we injected venom into the last abdominal ganglion of the cockroach, which houses a well-characterized cholinergic synapse. Injected venom abolishes both sensory-evoked and agonist-evoked postsynaptic potentials recorded in the postsynaptic neuron for 2 to 3 min without affecting action potential propagation. Thus, the venom blocking effect has a postsynaptic component that follows the same time course as the transient paralysis induced by the thoracic sting. Finally, injection of a nicotinic antagonist in the front thoracic ganglion induces paralysis of the front legs. We conclude that the transient paralytic effect of the thoracic sting can be mainly accounted for by the presence of a venom active component that induces a postsynaptic block of central cholinergic synaptic transmission.

Action Potentials↗
PubMed2006

Wasp venom injected into the prey's brain modulates thoracic identified monoaminergic neurons.

The wasp Ampulex compressa injects a cocktail of neurotoxins into the brain of its cockroach prey to induce an enduring change in the execution of locomotory behaviors. Our hypothesis is that the venom injected into the brain indirectly alters the activity of monoaminergic neurons, thus changing the levels of monoamines that tune the central synapses of locomotory circuits. The purpose of the present investigation was to establish whether the venom alters the descending control, from the brain, of octopaminergic neurons in the thorax. This question was approached by recording the activity of specific identified octopaminergic neurons after removing the input from the brain or after a wasp sting into the brain. We show that the activity of these neurons is altered in stung and "brainless" animals. The spontaneous firing rate of these neurons in stung and brainless animals is approximately 20% that in control animals. Furthermore, we show that an identified octopamine neuron responds more weakly both to sensory stimuli and to direct injection of current in all treated groups. The alteration in the activity of octopamine neurons is likely to be part of the mechanism by which the wasp induces a change in the behavioral state of its prey and also affects its metabolism by reducing the potent glycolytic activator fructose 2,6-bisphosphate in leg muscle. To our knowledge, this is the first direct evidence of a change in electrical activity of specific monoaminergic neurons that can be so closely associated with a venom-induced change in behavioral state of a prey animal.

Animals↗
PubMed2004

Structural characterization of novel chemotactic and mastoparan peptides from the venom of the social wasp Agelaiapallipes pallipes by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.

High-performance liquid chromatography/electrospray ionization mass spectrometry (HPLC/ESI-MS) and high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) techniques were applied for the detection, purification, monitoring, and sequencing of two novel and biologically active peptides occurring at very low levels in the venom of the wasp Agelaia pallipes pallipes. These peptides were sequenced under LC/ESI-MS/MS conditions and designated as Agelaia-CP (I/L-L-G-T-I-L-G-L-L-K-G-I/L-NH2, MW 1207.8 Da) and Agelaia-MP (I/L-N-W-L-K-L-G-K-A-I-I-D-A-I/L-NH2, MW 1565.0 Da). The peptide Agelaia-CP showed no hemolytic activity, but it behaved as a mast cell degranulator and induced a potent chemotaxis in polymorphonucleated leukocyte (PMNL) cells, typical of a wasp chemotactic peptide. The peptide Agelaia-MP showed both powerful mast cell degranulation and hemolysis of washed rat red blood cells, and is thus assigned as a new member of the mastoparan family of peptides. Both peptides seem to be directly involved in the strong inflammatory reactions associated with wasp stings.

Animals↗