title: Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3).
abstract: Secretion of cytolytic granules content at the immunological synapse is a highly regulated process essential for lymphocyte cytotoxicity. This process requires the rapid transfer of perforin containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane. Defective cytotoxicity characterizes a genetically heterogeneous condition named familial hemophagocytic lymphohistiocytosis (FHL), which can be associated with perforin deficiency. The locus of a perforin (+) FHL subtype (FHL3), observed in 10 patients, was mapped to 17q25. This region contains hMunc13-4, a member of the Munc13 family of proteins involved in vesicle priming function. HMunc13-4 mutations were shown to cause FHL3. HMunc13-4 deficiency results in defective cytolytic granule exocytosis, despite polarization of the secretory granules and docking with the plasma membrane. Expressed tagged hMunc13-4 localizes with cytotoxic granules at the immunological synapse. HMunc13-4 is therefore essential for the priming step of cytolytic granules secretion preceding vesicle membrane fusion.
authors: INSERM U429, Hôpital Necker-Enfants Malades, 75743 Paris, France.
authors: Jérôme
authors: J
authors: Feldmann
authors: Isabelle
authors: I
authors: Callebaut
authors: Graça
authors: G
authors: Raposo
authors: Stéphanie
authors: S
authors: Certain
authors: Delphine
authors: D
authors: Bacq
authors: Cécile
authors: C
authors: Dumont
authors: Nathalie
authors: N
authors: Lambert
authors: Marie
authors: M
authors: Ouachée-Chardin
authors: Gaëlle
authors: G
authors: Chedeville
authors: Hannah
authors: H
authors: Tamary
authors: Véronique
authors: V
authors: Minard-Colin
authors: Etienne
authors: E
authors: Vilmer
authors: Stéphane
authors: S
authors: Blanche
authors: Françoise
authors: F
authors: Le Deist
authors: Alain
authors: A
authors: Fischer
authors: Geneviève
authors: G
authors: de Saint Basile
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015550:Cell Degranulation; D016764:Cell Polarity; D002478:Cells, Cultured; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D005089:Exocytosis; D005260:Female; D020869:Gene Expression Profiling; D005816:Genetic Complementation Test; D015616:Histiocytosis, Non-Langerhans-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009928:Organ Specificity; D010375:Pedigree; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: D011506:Proteins; D012333:RNA, Messenger; C430713:Unc13d protein, rat