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A more recent version of this article appeared on February 1, 2005
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Submitted on October 22, 2004
Accepted on November 2, 2004
*Department of Cell Biology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; Institute of Biochemistry, Romanian Academy, 71102 Bucharest, Romania; Biomolecular Mass Spectrometry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands; ||Department of Pediatric Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; ¶Max Planck Institute for Experimental Medicine, D-37075 Göttingen, Germany
Monitoring Editor: Jennifer Lippincott-Schwartz
Griscelli syndrome type 2 (GS2) is a genetic disorder in which patients exhibit life-threatening defects of cytotoxic T lymphocytes (CTLs) whose lytic granules fail to dock on the plasma membrane and therefore do not release their contents. The disease is caused by the absence of functional rab27a, but how rab27a controls secretion of lytic granule contents remained elusive. Mutations in Munc13-4 cause Familial Hemophagocytic Lymphohistiocytosis subtype 3 (FHL3), a disease phenotypically related to GS2. We show that Munc13-4 is a direct partner of rab27a. The two proteins are highly expressed in CTLs and mast cells where they colocalized on secretory lysosomes. The region comprising the Munc13 Homology Domains is essential for the localization of Munc13-4 to secretory lysosomes. The GS2 mutant rab27aW73G had strongly reduced binding to Munc13-4, while the FHL3 mutant Munc13-4
608-611 failed to bind rab27a. Overexpression of Munc13-4 enhanced degranulation of secretory lysosomes in mast cells, showing that it has a positive regulatory role in secretory lysosome fusion. We suggest that the secretion defects seen in GS2 and FHL3 have a common origin and we propose that the rab27a/Munc13-4 complex is an essential regulator of secretory granule fusion with the plasma membrane in hematopoietic cells. Mutations in either of the two genes prevent formation of this complex, and abolish secretion.
These authors contributed equally to this work.
#Corresponding author.
E-mail: pvander{at}knoware.nl
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