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Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes.

Science immunology

Authors: Artem Kalinichenko, Jakob Huemer, Theresa Humer, Matthias Haimel, Michael Svaton, Nicolas Socquet-Juglard, Giovanna Perinetti Casoni, Celine Prakash, Maximilian von der Linde, Julia Pazmandi, Cheryl van de Wetering, Javier Nunez-Fontarnau, Anton Kamnev, Sarah Giuliani, Martin G Jaeger, Elisa Hahn, Sarah Dobner, Andrea Rukavina, Elise Sylvander, Jacqueline Seigner, Christina Rashkova, Birgit Hoeger, Michael W Traxlmayr, Manfred Lehner, Yenan T Bryceson, Janna Saarela, Thomas Hannich, Irinka Castanon, Georg Winter, Loïc Dupré, Kaan Boztug

Regulated exocytosis controls key cellular functions ranging from neurotransmitter release to the secretion of immune mediators, and its disruption is associated with numerous pathologies. The cytotoxic activity of lymphocytes is particularly dependent on regulated and polarized lytic granule delivery toward infected or malignant cells. Although genetic and mechanistic studies have identified factors regulating exocytosis in cytotoxic lymphocytes, a systematic mapping of the relevant factors and their relationships is lacking. Through a genome-scale CRISPR knockout screen in a human natural killer cell line, we characterized a complex genetic network regulating cytotoxic granule exocytosis, with lipid metabolism and protein lipidation among the most prominent pathways. By combining global protein palmitoylation and lipidomic studies, we found that ZDHHC17 drives palmitoylation of the core SNARE complex protein SNAP23 to target cytotoxic granules to GM1-rich lipid rafts whose assembly is controlled by serine palmitoyltransferase. In summary, our study identifies previously unrecognized factors essential for cytotoxic function in human lymphocytes and uncovers how lipid metabolism and protein palmitoylation are involved in the process of regulated exocytosis.

PMID: 41105755

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