Rapid intracellular transport and secretion of cytotoxic granules through the immunological synapse requires a balanced interaction of several proteins. Disturbance of this highly regulated process underlies familial hemophagocytic lymphohistiocytosis (FHL), a genetically heterogeneous autosomal-recessive disorder characterized by a severe hyperinflammatory phenotype. Here, we have assigned FHL-5 to a 1 Mb region on chromosome 19p by using high-resolution SNP genotyping in eight unrelated FHL patients from consanguineous families. Subsequently, we found nine different mutations, either truncating or missense, in STXBP2 in twelve patients from Turkey, Saudi Arabia, and Central Europe. STXBP2 encodes syntaxin binding protein 2 (Munc18-2), involved in the regulation of vesicle transport to the plasma membrane. We have identified syntaxin 11, a SNARE protein mutated in FHL-4, as an interaction partner of STXBP2. This interaction is eliminated by the missense mutations found in our FHL-5 patients, which leads to a decreased stability of both proteins, as shown in patient lymphocytes. Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis.

Eutrophication can play a central role in promoting harmful algal blooms (HABs), and therefore many HAB studies to date have focused on macronutrients (N, P, Si). Although a majority of algal species require exogenous B vitamins (i.e., auxotrophic for B vitamins), the possible importance of organic micronutrients such as B vitamins (B 1 , B 7 , B 12 ) in regulating HABs has rarely been considered. Prior investigations of vitamins and algae have examined a relatively small number of dinoflagellates (n = 26) and a paucity of HAB species (n = 4). In the present study, the vitamin B 1 , B 7 , and B 12 requirements of 41 strains of 27 HAB species (19 dinoflagellates) were investigated. All but one species (two strains) of harmful algae surveyed required vitamin B 12 , 20 of 27 species required B 1 , and 10 of 27 species required B 7 , all proportions higher than the previously reported for non-HAB species. Half-saturation (K s ) constants of several HAB species for B 1 and B 12 were higher than those previously reported for other phytoplankton and similar to vitamin concentrations reported in estuaries. Cellular quotas for vitamins suggest that, in some cases, HAB demands for vitamins may exhaust standing stocks of vitamins in hours to days. The sum of these findings demonstrates the potentially significant ecological role of B-vitamins in regulating the dynamics of HABs.H armful algal blooms (HABs) are a significant threat to coastal ecosystems, public health, economies, and fisheries, and there are strong links between nutrient loading and HABs within ecosystems around the world (1-3). Most studies of HABs focused on nutrients have primarily investigated the importance of macronutrients (N, P, Si) (2, 3). In contrast, the importance of coenzymes and particularly vitamins (vitamins B 1 , B 7 , and B 12 ) in regulating and stimulating HABs has rarely been considered. This omission is despite the fact that exogenous B vitamins are essential compounds for phytoplankton species that lack the required biosynthetic pathways to produce B vitamins, i.e., vitamin B-auxotrophy (4-10).Vitamin B 12 is essential for the synthesis of amino acids, deoxyriboses, and the reduction and transfer of single carbon fragments in many biochemical pathways (11, 12), whereas vitamin B 1 (thiamine) plays a pivotal role in intermediary carbon metabolism and is a cofactor for number of enzymes involved in primary carbohydrate and branched-chain amino acid metabolism (13,14). More than half of 326 algal species surveyed are auxotrophs for B 12 (10-12, 15) and more than 20% of the 306 microalgal species surveyed are auxotrophs for B 1 [compiled in Croft et al. (14)]. In addition, 5% of 306 algae surveyed require biotin (vitamin B 7 ), a cofactor of several essential carboxylase enzymes, such as acetyl CoA (14).Recently, there has been burgeoning interest in the ability of vitamins to regulate phytoplankton community growth and structure. Novel high performance liquid chromatography (HPLC) techniques for the direct measurement of vitamins B 1 and...

Harmful algal blooms (HABs) cause significant economic and ecological damage worldwide. Despite considerable efforts, a comprehensive understanding of the factors that promote these blooms has been lacking, because the biochemical pathways that facilitate their dominance relative to other phytoplankton within specific environments have not been identified. Here, biogeochemical measurements showed that the harmful alga Aureococcus anophagefferens outcompeted co-occurring phytoplankton in estuaries with elevated levels of dissolved organic matter and turbidity and low levels of dissolved inorganic nitrogen. We subsequently sequenced the genome of A. anophagefferens and compared its gene complement with those of six competing phytoplankton species identified through metaproteomics. Using an ecogenomic approach, we specifically focused on gene sets that may facilitate dominance within the environmental conditions present during blooms. A. anophagefferens possesses a larger genome (56 Mbp) and has more genes involved in light harvesting, organic carbon and nitrogen use, and encoding selenium- and metal-requiring enzymes than competing phytoplankton. Genes for the synthesis of microbial deterrents likely permit the proliferation of this species, with reduced mortality losses during blooms. Collectively, these findings suggest that anthropogenic activities resulting in elevated levels of turbidity, organic matter, and metals have opened a niche within coastal ecosystems that ideally suits the unique genetic capacity of A. anophagefferens and thus, has facilitated the proliferation of this and potentially other HABs.

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Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically determined