Fish-hunting cone snail disrupts prey’s glucose homeostasis with weaponized mimetics of somatostatin and insulin

Ho Yan Yeung, Iris Bea L. Ramiro, Daniel B. Andersen, Thomas Lund Koch, Alexander Hamilton, Walden E. Bjørn-Yoshimoto, Samuel Espino, Sergey Y. Vakhrushev, Kasper B. Pedersen, Noortje Haan, Agnes L. Hipgrave Ederveen, Baldomero M. Olivera, Jakob G. Knudsen, Hans Bräuner-Osborne, Katrine T. Schjoldager, Jens Juul Holst and Helena Safavi-Hemami ()
Additional contact information
Ho Yan Yeung: University of Copenhagen
Iris Bea L. Ramiro: University of Copenhagen
Daniel B. Andersen: University of Copenhagen
Thomas Lund Koch: University of Copenhagen
Alexander Hamilton: University of Copenhagen
Walden E. Bjørn-Yoshimoto: University of Copenhagen
Samuel Espino: University of Utah
Sergey Y. Vakhrushev: University of Copenhagen
Kasper B. Pedersen: University of Copenhagen
Noortje Haan: Center for Proteomics and Metabolomics
Agnes L. Hipgrave Ederveen: Center for Proteomics and Metabolomics
Baldomero M. Olivera: University of Utah
Jakob G. Knudsen: University of Copenhagen
Hans Bräuner-Osborne: University of Copenhagen
Katrine T. Schjoldager: University of Copenhagen
Jens Juul Holst: University of Copenhagen
Helena Safavi-Hemami: University of Copenhagen

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Venomous animals have evolved diverse molecular mechanisms to incapacitate prey and defend against predators. Most venom components disrupt nervous, locomotor, and cardiovascular systems or cause tissue damage. The discovery that certain fish-hunting cone snails use weaponized insulins to induce hypoglycemic shock in prey highlights a unique example of toxins targeting glucose homeostasis. Here, we show that, in addition to insulins, the deadly fish hunter, Conus geographus, uses a selective somatostatin receptor 2 (SSTR2) agonist that blocks the release of the insulin-counteracting hormone glucagon, thereby exacerbating insulin-induced hypoglycemia in prey. The native toxin, Consomatin nG1, exists in several proteoforms with a minimized vertebrate somatostatin-like core motif connected to a heavily glycosylated N-terminal region. We demonstrate that the toxin’s N-terminal tail closely mimics a glycosylated somatostatin from fish pancreas and is crucial for activating the fish SSTR2. Collectively, these findings provide a stunning example of chemical mimicry, highlight the combinatorial nature of venom components, and establish glucose homeostasis as an effective target for prey capture.

Date: 2024
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DOI: 10.1038/s41467-024-50470-2

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