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Abstract
Natural Killer (NK) cells and Cytotoxic T lymphocytes (CTL) are critical for the immune response against virus infections or transformed cells. They kill target cells via polarized exocytosis of lytic proteins from secretory lysosomes (SL). Rab27a and munc13-4 interact directly and are required for target cell killing. How they cooperate in the intricate degranulation process is not known. We identified critical residues in munc13-4 for rab27 interaction and tested binding mutants in several complementation assays. In a rat mast cell line we replaced endogenous munc13-4 with ectopically expressed munc13-4 constructs. Unlike wild type munc13-4, binding mutants fail to rescue β-hexosaminidase secretion. In accord, expression of binding mutants in CTL of Familial Hemophagocytic Lymphohistiocytosis type 3 patients, does not rescue CD107 appearance on the plasma membrane. Total Internal Reflection Fluorescence (TIRF) imaging shows that munc13-4*rab27a restricts motility of SL in the subapical cytoplasm. We propose that rab27*munc13-4 tethers SL to the plasma membrane, a requirement for formation of a cognate SNARE complex for fusion.
Acknowledgments
The study was supported by grants of the Dutch Cancer Society Koningin Wilhelmina Fonds (PvdS), the French National Institute for Health and Medical Research (INSERM), the French National Research Agency (ANR) and the Fondation pour la Recherche Médicale (FRM). NN is supported by a postdoctoral fellowship from l’Association de Recherche contre le cancer (ARC). We thank Rene Scriwanek for help with preparation of figures.
Conflict of interest disclosure
The authors declare no competing financial and scientific interests.