Specialized insulin is used for chemical warfare by fish-hunting cone snails

Abstract

More than 100 species of venomous cone snails (genus Conus) are highly effective predators of fish. The vast majority of venom components identified and functionally characterized to date are neurotoxins specifically targeted to receptors, ion channels, and transporters in the nervous system of prey, predators, or competitors. Here we describe a venom component targeting energy metabolism, a radically different mechanism. Two fish-hunting cone snails, Conus geographus and Conus tulipa, have evolved specialized insulins that are expressed as major components of their venoms. These insulins are distinctive in having much greater similarity to fish insulins than to the molluscan hormone and are unique in that posttranslational modifications characteristic of conotoxins (hydroxyproline, γ-carboxyglutamate) are present. When injected into fish, the venom insulin elicits hypoglycemic shock, a condition characterized by dangerously low blood glucose. Our evidence suggests that insulin is specifically used as a weapon for prey capture by a subset of fish-hunting cone snails that use a net strategy to capture prey. Insulin appears to be a component of the nirvana cabal, a toxin combination in these venoms that is released into the water to disorient schools of small fish, making them easier to engulf with the snail's distended false mouth, which functions as a net. If an entire school of fish simultaneously experiences hypoglycemic shock, this should directly facilitate capture by the predatory snail.insulin shock | cone snails | conotoxins | nirvana cabal | venom

A Hepatocyte FOXN3-α Cell Glucagon Axis Regulates Fasting Glucose

“…Finally, we measured foxn3 transcripts in zebrafish injected with vehicle or streptozotocin (STZ) to gauge the rapidity of foxn3 downregulation in response to unopposed endogenous glucagon action. Twenty-four hours following a single STZ treatment, blood glucose levels were significantly increased from 67 ± 6 mg/dL to 270 ± 34 mg/dL (p < 0.01; Safavi-Hemami et al, 2015); liver foxn3 transcript abundance in these animals was decreased by STZ treatment (Figure 1F). …”

An efficient transcriptome analysis pipeline to accelerate venom peptide discovery and characterisation

“…Our reanalysis discovered more 'I4' superfamily sequences and reclassified these into the I2 superfamily. A closer inspection of the reported novel Y2 superfamily sequences revealed that they were also misclassified (Safavi-Hemami et al, 2015) and belonged to the recently described coninsulin class (Figure 2). The H2 superfamily described by Lavergne et al comprised one transcript with a single read that was identical to the peptide Mr3.8 belonging to the M superfamily with the exception of the first few residues of the reported signal sequence .…”

“…Though this program can handle large datasets, an overreliance on such programs can miss novel toxin sequences that frequently possess novel cysteine scaffolds. It can also lead to incorrect annotations, such as the Coninsulins from Conus geographus being misidentified as a novel conotoxin gene superfamily (Safavi-Hemami et al, 2015).…”

Hormone-like peptides in the venoms of marine cone snails

“…2000 platform at Cofactor Genomics as described previously (Safavi-Hemami et al, 2015). Reads were de novo assembled using Trinity (Grabherr et al, 2011) and annotated using BLASTx.…”

“…Examples include the conopressins (vasopressin analogues) from Conus geographus and Conus striatus (Cruz et al, 1987), contulakin-G (a neurotensin analogue) from C. geographus (Craig et al, 1999), RFamide neuropeptides from Conus spurius and Conus victoriae (Maillo et al, 2002; Robinson et al, 2015), conomap (a myoactive tetradecapeptide) from Conus vitulinus (Dutertre et al, 2006), conoCAPs (analogues of crustacean cardioactive peptide) from Conus villepinii (Möller et al, 2010) and neuropeptide-F/Y from Conus betulinus (Wu et al, 2010). Furthermore, we recently demonstrated that specialised insulins are an abundant and active component of some Conus venoms (Safavi-Hemami et al, 2015). When injected into fish, the venom insulin elicits hypoglycemic shock, thus facilitating capture of the physiologically impaired prey.…”