Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes

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.

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Publication Details

Journal
Science Immunology
Published
2025-10-17
DOI
https://doi.org/10.1126/sciimmunol.ado3825
Citations
1
Primary Topic
Cellular transport and secretion
Type
article
Field-Weighted Citation Impact
1.15
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article

Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes

Theresa Humer, Anton Kamnev, Jacqueline Seigner, Georg E. Winter et al.
1 citations
Science Immunology
Cellular transport and secretion
1.15
article

Protein palmitoylation and sphingolipid metabolism control regulated exocytosis in cytotoxic lymphocytes

Theresa Humer, Anton Kamnev, Jacqueline Seigner, Georg E. Winter, Birgit Hoeger, Andrea Rukavina, Júlia Pázmándi, Elise Sylvander, Elisa Hahn, Celine Prakash, Manfred Lehner, Yenan T. Bryceson, Matthias Haimel, Maximilian von der Linde, Javier Núñez-Fontarnau, Christina Rashkova, Loı̈c Dupré, Irinka Castanon, Kaan Boztuǧ, Cheryl van de Wetering, Sarah Giuliani, Jakob Huemer, Artem Kalinichenko, Michael W. Traxlmayr, Janna Saarela, J. Thomas Hannich, Michael Svatoň, Giovanna Perinetti Casoni, Martin G. Jaeger, Sarah Dobner, Nicolas Socquet-Juglard
article en
1 citations

Abstract

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.

Science ImmunologyVol. 10(112)
Johannes Kepler University of Linz (AT), Oslo University Hospital (NO), Centre National de la Recherche Scientifique (FR), Université Toulouse III - Paul Sabatier (FR), Austrian Academy of Sciences (AT), Inserm (FR), University of Oslo (NO), Medical University of Graz (AT), University Hospital Bonn (DE), Karolinska Institutet (SE), Ludwig Boltzmann Institute for Age Research (AT), Christian Doppler Laboratory for Thermoelectricity (AT), St Anna Children's Hospital (AT), CeMM Research Center for Molecular Medicine (AT), Cancer Registry of Norway (NO), Institute for Molecular Medicine Finland (FI), Ludwig Boltzmann Institute Applied Diagnostics (AT), Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (AT), Ludwig Boltzmann Institute for Cancer Research (AT), St. Anna Children's Cancer Research Institute, University of Bergen (NO), Medical University of Vienna (AT), BOKU University (AT)
Openalex Percentile: Top 19%
Cellular transport and secretion
1.15
DOISourceOpenAlex
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