Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3)

被引:714
作者
Feldmann, J
Callebaut, I
Raposo, G
Certain, S
Bacq, D
Dumont, C
Lambert, N
Ouachée-Chardin, M
Chedeville, G
Tamary, H
Minard-Colin, V
Vilmer, E
Blanche, S
Le Deist, F
Fischer, A
Saint Basile, GD [1 ]
机构
[1] Hop Necker Enfants Malad, INSERM U429, F-75743 Paris, France
[2] Univ Paris 06, CNRS UMR7590, LMCP, F-75005 Paris, France
[3] Univ Paris 07, CNRS UMR7590, LMCP, F-75005 Paris, France
[4] Inst Curie, CNRS UMR 144, Paris, France
[5] Ctr Natl Genotypage, F-91057 Evry, France
[6] Hop Necker Enfants Malad, Unite Immunol Hematol, F-75015 Paris, France
[7] Schneiders Children Med Ctr, Pediat Hematol Unit, IL-49202 Petah Tiqwa, Israel
[8] Hop Robert Debre, Unite Immunohematol, F-75019 Paris, France
关键词
D O I
10.1016/S0092-8674(03)00855-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:461 / 473
页数:13
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