Dataset Information

Mammalian Solute Carrier (SLC)-like transporters of Legionella pneumophila.

ABSTRACT: Acquisition of nutrients during intra-vacuolar growth of L. pneumophila within macrophages or amoebae is poorly understood. Since many genes of L. pneumophila are acquired by inter-kingdom horizontal gene transfer from eukaryotic hosts, we examined the presence of human solute carrier (SLC)-like transporters in the L. pneumophila genome using I-TASSER to assess structural alignments. We identified 11 SLC-like putative transporters in L. pneumophila that are structurally similar to SLCs, eight of which are amino acid transporters, and one is a tricarboxylate transporter. The two other transporters, LstA and LstB, are structurally similar to the human glucose transporter, SLC2a1/Glut1. Single mutants of lstA or lstB have decreased ability to import, while the lstA/lstB double mutant is severely defective for uptake of glucose. While lstA or lstB single mutants are not defective in intracellular proliferation within Acanthamoeba polyphaga and human monocyte-derived macrophages, the lstA/lstB double mutant is severely defective in both host cells. The two phenotypic defects of the lstA/lstB double mutant in uptake of glucose and intracellular replication are both restored upon complementation of either lstA or lstB. Our data show that the two glucose transporters, LstA and LstB, are redundant and are required for intracellular replication within human macrophages and amoebae.

SUBMITTER: Best A

PROVIDER: S-EPMC5974234 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Mammalian Solute Carrier (SLC)-like transporters of Legionella pneumophila.

Best Ashley A Jones Snake S Abu Kwaik Yousef Y

Scientific reports 20180529 1

Acquisition of nutrients during intra-vacuolar growth of L. pneumophila within macrophages or amoebae is poorly understood. Since many genes of L. pneumophila are acquired by inter-kingdom horizontal gene transfer from eukaryotic hosts, we examined the presence of human solute carrier (SLC)-like transporters in the L. pneumophila genome using I-TASSER to assess structural alignments. We identified 11 SLC-like putative transporters in L. pneumophila that are structurally similar to SLCs, eight of ...[more]

PMID: 29844490

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Project description:The human solute carrier (SLC) superfamily of transporters is comprised of over 400 membrane-bound proteins, and plays essential roles in a multitude of physiological and pharmacological processes. In addition, perturbation of SLC transporter function underlies numerous human diseases, which renders SLC transporters attractive drug targets. Common genetic polymorphisms in SLC genes have been associated with inter-individual differences in drug efficacy and toxicity. However, despite their tremendous clinical relevance, epidemiological data of these variants are mostly derived from heterogeneous cohorts of small sample size and the genetic SLC landscape beyond these common variants has not been comprehensively assessed. In this study, we analyzed Next-Generation Sequencing data from 141,456 individuals from seven major human populations to evaluate genetic variability, its functional consequences, and ethnogeographic patterns across the entire SLC superfamily of transporters. Importantly, of the 204,287 exonic single-nucleotide variants (SNVs) which we identified, 99.8% were present in less than 1% of analyzed alleles. Comprehensive computational analyses using 13 partially orthogonal algorithms that predict the functional impact of genetic variations based on sequence information, evolutionary conservation, structural considerations, and functional genomics data revealed that each individual genome harbors 29.7 variants with putative functional effects, of which rare variants account for 18%. Inter-ethnic variability was found to be extensive, and 83% of deleterious SLC variants were only identified in a single population. Interestingly, population-specific carrier frequencies of loss-of-function variants in SLC genes associated with recessive Mendelian disease recapitulated the ethnogeographic variation of the corresponding disorders, including cystinuria in Jewish individuals, type II citrullinemia in East Asians, and lysinuric protein intolerance in Finns, thus providing a powerful resource for clinical geneticists to inform about population-specific prevalence and allelic composition of Mendelian SLC diseases. In summary, we present the most comprehensive data set of SLC variability published to date, which can provide insights into inter-individual differences in SLC transporter function and guide the optimization of population-specific genotyping strategies in the bourgeoning fields of personalized medicine and precision public health.

Dataset Information

Mammalian Solute Carrier (SLC)-like transporters of Legionella pneumophila.

Publications

Mammalian Solute Carrier (SLC)-like transporters of Legionella pneumophila.

Similar Datasets

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