Siglec-6 mediates the uptake of extracellular vesicles through a noncanonical glycolipid binding pocket

Edward N. Schmidt, Dimitra Lamprinaki, Kelli A. McCord, Maju Joe, Mirat Sojitra, Ayk Waldow, Jasmine Nguyen, John Monyror, Elena N. Kitova, Fahima Mozaneh, Xue Yan Guo, Jaesoo Jung, Jhon R. Enterina, Gour C. Daskhan, Ling Han, Amanda R. Krysler, Christopher R. Cromwell, Basil P. Hubbard, Lori J. West, Marianne Kulka, Simonetta Sipione, John S. Klassen, Ratmir Derda, Todd L. Lowary, Lara K. Mahal, Meghan R. Riddell and Matthew S. Macauley ()
Additional contact information
Edward N. Schmidt: University of Alberta
Dimitra Lamprinaki: University of Alberta
Kelli A. McCord: University of Alberta
Maju Joe: University of Alberta
Mirat Sojitra: University of Alberta
Ayk Waldow: University of Alberta
Jasmine Nguyen: Department of Obstetrics & Gynaecology and Physiology University of Alberta
John Monyror: University of Alberta
Elena N. Kitova: University of Alberta
Fahima Mozaneh: University of Alberta
Xue Yan Guo: University of Alberta
Jaesoo Jung: University of Alberta
Jhon R. Enterina: University of Alberta
Gour C. Daskhan: University of Alberta
Ling Han: University of Alberta
Amanda R. Krysler: University of Alberta
Christopher R. Cromwell: University of Alberta
Basil P. Hubbard: University of Alberta
Lori J. West: University of Alberta
Marianne Kulka: University of Alberta
Simonetta Sipione: University of Alberta
John S. Klassen: University of Alberta
Ratmir Derda: University of Alberta
Todd L. Lowary: University of Alberta
Lara K. Mahal: University of Alberta
Meghan R. Riddell: Department of Obstetrics & Gynaecology and Physiology University of Alberta
Matthew S. Macauley: University of Alberta

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Immunomodulatory Siglecs are controlled by their glycoprotein and glycolipid ligands. Siglec-glycolipid interactions are often studied outside the context of a lipid bilayer, missing the complex behaviors of glycolipids in a membrane. Through optimizing a liposomal formulation to dissect Siglec–glycolipid interactions, it is shown that Siglec-6 can recognize glycolipids independent of its canonical binding pocket, suggesting that Siglec-6 possesses a secondary binding pocket tailored for recognizing glycolipids in a bilayer. A panel of synthetic neoglycolipids is used to probe the specificity of this glycolipid binding pocket on Siglec-6, leading to the development of a neoglycolipid with higher avidity for Siglec-6 compared to natural glycolipids. This neoglycolipid facilitates the delivery of liposomes to Siglec-6 on human mast cells, memory B-cells and placental syncytiotrophoblasts. A physiological relevance for glycolipid recognition by Siglec-6 is revealed for the binding and internalization of extracellular vesicles. These results demonstrate a unique and physiologically relevant ability of Siglec-6 to recognize glycolipids in a membrane.

Date: 2023
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DOI: 10.1038/s41467-023-38030-6

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