Disease relevance of UNC13D

• Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3) [1].
• Because these patients may develop the disease during adolescence or even later, haematologists should include FHL2 and FHL3 in the differential diagnosis of young adults with fever, cytopenia, splenomegaly and hypercytokinaemia [2].
• These observations decisively prove that Rab27a is involved in CFTR channel regulation through protein-protein interactions involving Munc13-4 and SLP-5 effector proteins, and thus could be a potential target for cystic fibrosis therapy [3].

High impact information on UNC13D

• This region contains hMunc13-4, a member of the Munc13 family of proteins involved in vesicle priming function [1].
• In this issue of Cell, Feldmann et al. identify mutations in Munc13-4 as a cause of familial hemophagocytic lymphohistiocytosis [4].
• Munc13-4 appears to be involved in the priming of cytotoxic granules prior to fusion with the plasma membrane [4].
• In addition, the demonstration of a direct interaction in vitro between Rab27a and Munc13-4 suggests the possibility that the Rab27a-Munc13-4 cascade might regulate CTL exocytosis by engaging SNAREs such as syntaxin11 [5].
• Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease [6].

Associations of UNC13D with chemical compounds

• The fMLF-induced translocation of Munc13-4 is strictly dependent on calcium in neutrophils [7].

Biological context of UNC13D

• Defective granule exocytosis caused by mutations in the hMunc13-4 gene (UNC13D) has been described in FHL-3 [8].
• Our findings demonstrate extensive genetic and allelic heterogeneity in FHL and delineate an approach for functionally characterizing missense mutations in RAB27A and UNC13D [8].
• Thus, Rab27 regulates the dense core granule secretion in platelets by employing its binding protein, Munc13-4 [9].
• As both STX11 and UNC13D are involved in vesicle trafficking and membrane fusion, we conclude that, besides mutations in perforin 1, defects in the endocytotic or the exocytotic pathway may be a common mechanism in FHL [10].

Anatomical context of UNC13D

• Using Rab27a affinity chromatography, we purified Munc 13-4 as a novel Rab27a interacting protein from platelet cytosol [11].

Other interactions of UNC13D

• Munc13-4 is a GTP-Rab27-binding protein regulating dense core granule secretion in platelets [9].
• We analyzed a large group of 63 unrelated patients with FHL of different geographic origins (Turkey:32; Germany:23; others:8) for mutations in STX11, PRF1, and UNC13D [8].
• We identified mutations in 38 samples (20 in PRF1, 12 in UNC13D, and six in STX11) [8].
• Furthermore, we affinity-purified a GTP-Rab27A-binding protein in platelets and identified it as Munc13-4, a homologue of Munc13-1 known as a priming factor for neurotransmitter release [9].
• Thus, FHL-2, FHL-3, and FHL-4 account for 80% of the HLH cases of Turkish origin, and for 30% of German patients [8].

Analytical, diagnostic and therapeutic context of UNC13D

• The immunoprecipitation experiments suggest that in the presence of excessive Munc13-4 and SLP-5 proteins, Rab27a interaction with ENaC is diminished [12].

References