Snake venom cardiotoxin can rapidly induce actin polymerization in intact platelets.
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ABSTRACT:
SUBMITTER: Liou RF
PROVIDER: S-EPMC1132315 | biostudies-other | 1993 Mar
REPOSITORIES: biostudies-other
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Project description:BackgroundWhile many studies have shown that extracellular proteins evolve rapidly, how selection acts on them remains poorly understood. We used snake venoms to understand the interaction between ecology, expression level, and evolutionary rate in secreted protein systems. Venomous snakes employ well-integrated systems of proteins and organic constituents to immobilize prey. Venoms are generally optimized to subdue preferred prey more effectively than non-prey, and many venom protein families manifest positive selection and rapid gene family diversification. Although previous studies have illuminated how individual venom protein families evolve, how selection acts on venoms as integrated systems, is unknown.ResultsUsing next-generation transcriptome sequencing and mass spectrometry, we examined microevolution in two pitvipers, allopatrically separated for at least 1.6 million years, and their hybrids. Transcriptomes of parental species had generally similar compositions in regard to protein families, but for a given protein family, the homologs present and concentrations thereof sometimes differed dramatically. For instance, a phospholipase A2 transcript comprising 73.4 % of the Protobothrops elegans transcriptome, was barely present in the P. flavoviridis transcriptome (<0.05 %). Hybrids produced most proteins found in both parental venoms. Protein evolutionary rates were positively correlated with transcriptomic and proteomic abundances, and the most abundant proteins showed positive selection. This pattern holds with the addition of four other published crotaline transcriptomes, from two more genera, and also for the recently published king cobra genome, suggesting that rapid evolution of abundant proteins may be generally true for snake venoms. Looking more broadly at Protobothrops, we show that rapid evolution of the most abundant components is due to positive selection, suggesting an interplay between abundance and adaptation.ConclusionsGiven log-scale differences in toxin abundance, which are likely correlated with biosynthetic costs, we hypothesize that as a result of natural selection, snakes optimize return on energetic investment by producing more of venom proteins that increase their fitness. Natural selection then acts on the additive genetic variance of these components, in proportion to their contributions to overall fitness. Adaptive evolution of venoms may occur most rapidly through changes in expression levels that alter fitness contributions, and thus the strength of selection acting on specific secretome components.
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Project description:Key innovations provide ecological opportunity by enabling access to new resources, colonization of new environments, and are associated with adaptive radiation. The most well-known pattern associated with adaptive radiation is an early burst of phenotypic diversification. Venoms facilitate prey capture and are widely believed to be key innovations leading to adaptive radiation. However, few studies have estimated their evolutionary rate dynamics. Here, we test for patterns of adaptive evolution in venom gene expression data from 52 venomous snake species. By identifying shifts in tempo and mode of evolution along with models of phenotypic evolution, we show that snake venom exhibits the macroevolutionary dynamics expected of key innovations. Namely, all toxin families undergo shifts in their rates of evolution, likely in response to changes in adaptive optima. Furthermore, we show that rapid-pulsed evolution modelled as a Lévy process better fits snake venom evolution than conventional early burst or Ornstein-Uhlenbeck models. While our results support the idea of snake venom being a key innovation, the innovation of venom chemistry lacks clear mechanisms that would lead to reproductive isolation and thus adaptive radiation. Therefore, the extent to which venom directly influences the diversification process is still a matter of contention.
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Project description:Bitis arietans is a snake of medical importance found throughout sub-Saharan Africa and in savannas and pastures of Morocco and western Arabia. The effects of its venom are characterized by local and systemic alterations, such as inflammation and cardiovascular and hemostatic disturbances, which can lead to victims' death or permanent disability. To better characterize the inflammatory process induced by this snake's venom, the participation of eicosanoids and PAF (platelet- activating factor) in this response were demonstrated in a previous study. In addition, edema and early increased vascular permeability followed by an accumulation of polymorphonuclear (PMN) cells in the peritoneal cavity were accompanied by the production of the eicosanoids LTB4, LTC4, TXB2, and PGE2, and local and systemic production of IL-6 and MCP-1. In this context, the present study focused on the identification of inflammatory mediators produced by human macrophages derived from THP-1 cells in response to Bitis arietans venom (BaV), and Kn-Ba, a serine protease purified from this venom. Here, we show that Kn-Ba, and even the less intensive BaV, induced the production of the cytokine TNF and the chemokines RANTES and IL-8. Only Kn-Ba was able to induce the production of IL-6, MCP-1, and IP-10, whereas PGE2 was produced only in response to BaV. Finally, the release of IL-1β in culture supernatants suggests the activation of the inflammasomes by the venom of Bitis arietans and by Kn-Ba, which will be investigated in more detail in future studies.
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Project description:Venomous snakebites can induce local tissue damage, including necrosis of soft tissues, haemorrhage, blistering and local swelling associated with plasma extravasation, which can lead to lethal complications such as hypovolemic shock. However, the details of the underlying mechanisms remain unknown. In this study, we showed that intradermal treatment of mice with venom rhodocytin from the Malayan viper Calloselasma rhodostoma induced plasma extravasation, dependent on C-type lectin-like receptor 2 (CLEC-2) on platelets. Rhodocytin-induced plasma extravasation also relied on mast cells and histamine. In vitro co-culture of rhodocytin-activated platelets with mast cells induced histamine release from mast cells in an ATP/P2X7-dependent manner. Consistent with this, blockade or deficiency of P2X7 in mast cells suppressed rhodocytin-induced plasma extravasation in the skin. Together, these findings indicate that rhodocytin induces plasma extravasation by triggering platelet activation via CLEC-2, followed by activation of mast cells and histamine release via the ATP/P2X7 pathway. These results reveal a previously unrecognized mechanism by which snake venom increases vascular permeability via complex venom toxin-mediated interactions between platelets and mast cells.
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Project description:Controlling perioperative bleeding is of critical importance to minimize hemorrhaging and fatality. Patients on anticoagulant therapy such as heparin have diminished clotting potential and are at risk for hemorrhaging. Here we describe a self-assembling nanofibrous peptide hydrogel (termed SLac) that on its own can act as a physical barrier to blood loss. SLac was loaded with snake-venom derived Batroxobin (50 ?g/mL) yielding a drug-loaded hydrogel (SB50). SB50 was potentiated to enhance clotting even in the presence of heparin. In vitro evaluation of fibrin and whole blood clotting helped identify appropriate concentrations for hemostasis in vivo. Batroxobin-loaded hydrogels rapidly (within 20s) stop bleeding in both normal and heparin-treated rats in a lateral liver incision model. Compared to standard of care, Gelfoam, and investigational hemostats such as Puramatrix, only SB50 showed rapid liver incision hemostasis post surgical application. This snake venom-loaded peptide hydrogel can be applied via syringe and conforms to the wound site resulting in hemostasis. This demonstrates a facile method for surgical hemostasis even in the presence of anticoagulant therapies.
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Project description:Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase and observed their rapid extension in number and length upon genotoxic treatments, frequently taking contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork remodeling is linked to deregulated chromatin loading of PrimPol, which promotes unrestrained and discontinuous DNA synthesis and limits the recruitment of RAD51 and SMARCAL1 to nascent DNA. Moreover, defective nuclear actin polymerization upon mild replication interference induces chromosomal instability in a PRIMPOL-dependent manner. Hence, by limiting PrimPol activity, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.
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Project description:Erabutoxins a and b are neurotoxins isolated from venom of a sea snake Laticauda semifasciata (erabu-umihebi). Amino acid sequences of the toxins indicated that the toxins are members of a superfamily consisting of short and long neurotoxins and cytotoxins found in sea snakes and terrestrial snakes. The short neurotoxins to which erabutoxins belong act by blocking the nicotinic acetylcholine receptor on the post synaptic membrane in a manner similar to that of curare. X-ray crystallography and NMR analyses showed that the toxins have a three-finger structure, in which three fingers made of three loops emerging from a dense core make a gently concave surface of the protein. The sequence comparison and the location of essential residues on the protein suggested the mechanism of binding of the toxin to the acetylcholine receptor. Classification of snakes by means of sequence comparison and that based on different morphological features were inconsistent, which led the authors to propose a hypothesis "Evolution without divergence."
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Project description:Three prothrombin activators; ecarin, which was originally isolated from the venom of the saw-scaled viper Echis carinatus, trocarin from the rough-scaled snake Tropidechis carinatus, and oscutarin from the Taipan snake Oxyuranus scutellatus, were expressed in mammalian cells with the purpose to obtain recombinant prothrombin activators that could be used to convert prothrombin to thrombin. We have previously reported that recombinant ecarin can efficiently generate thrombin without the need for additional cofactors, but does not discriminate non-carboxylated prothrombin from biologically active ?-carboxylated prothrombin. Here we report that recombinant trocarin and oscutarin could not efficiently generate thrombin without additional protein co-factors. We confirm that both trocarin and oscutarin are similar to human coagulation Factor X (FX), explaining the need for additional cofactors. Sequencing of a genomic fragment containing 7 out of the 8 exons coding for oscutarin further confirmed the similarity to human FX.
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Project description:Nemaline myopathy (NM) is one of the most common forms of congenital myopathy and it is identified by the presence of "nemaline bodies" (rods) in muscle fibers by histopathological examination. The most common forms of NM are caused by mutations in the Actin Alpha 1 (ACTA1) and Nebulin (NEB) genes. Clinical features include hypotonia and muscle weakness. Unfortunately, there is no curative treatment and the pathogenetic mechanisms remain unclear. In this manuscript, we examined the pathophysiological alterations in NM using dermal fibroblasts derived from patients with mutations in ACTA1 and NEB genes. Patients' fibroblasts were stained with rhodamine-phalloidin to analyze the polymerization of actin filaments by fluorescence microscopy. We found that patients' fibroblasts showed incorrect actin filament polymerization compared to control fibroblasts. Actin filament polymerization defects were associated with mitochondrial dysfunction. Furthermore, we identified two mitochondrial-boosting compounds, linoleic acid (LA) and L-carnitine (LCAR), that improved the formation of actin filaments in mutant fibroblasts and corrected mitochondrial bioenergetics. Our results indicate that cellular models can be useful to study the pathophysiological mechanisms involved in NM and to find new potential therapies. Furthermore, targeting mitochondrial dysfunction with LA and LCAR can revert the pathological alterations in NM cellular models.
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Project description:Venom composition varies across snakes from all taxonomic levels and is influenced by the snakes’ age, habitat, diet, and sexual dimorphism. The present study reports the first in-depth investigation of venom composition in male and female Bothrops moojeni (B. moojeni) snakes (BmooM and BmooF, respectively) through three proteomics approaches associated with functional, cytotoxic, and immunoreactivity characterization. Compared with BmooM venom, BmooF venom exhibited weaker hyaluronidase, metalloproteinase, and phospholipase activity; stronger recognition by anti-bothropic serum; 1.4-fold stronger cytotoxicity; and greater number of peptides. The increased L-amino acid oxidase expression probably accounted for the stronger immunoreactivity and cytotoxicity of BmooF venom. BmooF and BmooM venom shared only 19% peptides. Some venom components were gender-specific, such as phospholipases B, phospholipase inhibitor, and hyaluronidases in BmooM, and cysteine-rich secretory proteins in BmooF. In conclusion, we describe herein the first proteomics study of B. moojeni snake venom and an in-depth characterization of gender-specific differences in venom composition. Altogether, our findings not only stress the importance of considering the snake’s gender during antivenom production, but also help to identify new potential drugs and biotechnological tools.
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