The late embryogenesis abundant (LEA) family is composed of a diverse collection of multidomain and multifunctional proteins found in all three domains of the tree of life, but they are particularly common in plants. Most members of the family are known to play an important role in abiotic stress response and stress tolerance in plants but are also part of the plant hypersensitive response to pathogen infection. The mechanistic basis for LEA protein functionality is still poorly understood. The group of LEA 2 proteins harbor one or more copies of a unique domain, the ater stress andpersensitive response (WHy) domain. This domain sequence has recently been identified as a unique open reading frame (ORF) in some bacterial genomes (mostly in the phylum ), and the recombinant bacterial WHy protein has been shown to exhibit a stress tolerance phenotype in and an protein denaturation protective function. Multidomain phylogenetic analyses suggest that the WHy protein gene sequence may have ancestral origins in the domain, with subsequent acquisition in and eukaryotes via endosymbiont or horizontal gene transfer mechanisms. Here, we review the structure, function, and nomenclature of LEA proteins, with a focus on the WHy domain as an integral component of the LEA constructs and as an independent protein.
The polymorphism rs2569190 within the CD14 endotoxin (lipopolysaccharide, LPS) receptor gene is associated with various disease conditions that are assumed to rely on endotoxin sensitivity. In vitro experiments suggest that the T allele sensitizes the host for exogenous or endogenous LPS via an enhanced CD14 expression. To prove the impact of this single nucleotide polymorphism in its natural genomic context in vivo, two parameters of gene transcription were analyzed in peripheral blood mononuclear cells (PBMC) from single healthy individuals: (a) recruitment of RNA polymerase II by haplotype-specific chromatin immunoprecipitation and (b) the relative amount of transcripts by allele-specific transcript quantification (ASTQ). RNA polymerase II was found to be twice as much bound to the most prevalent haplotype, C-T-C-G, the only one carrying a T at the position rs2569190 of interest. ASTQ employing two independent read-out assays revealed, however, similar transcript numbers originating from C-T-C-G and non-C-T-C-G haplotypes. Total CD14 mRNA levels from freshly isolated PBMC, moreover, were neither related to donors' geno-nor haplogenotypes. Our data argue for a functional impact of the rs2569190 polymorphism in terms of a stronger transcription initiation on T allele gene variants even if preferential allele-specific binding does not result in an increase in transcript numbers. Endotoxin sensitivity associated with this genetic variation appears not to rely solely on a cis-acting regulatory impact of rs2569190 on CD14 gene transcription in PBMC.
Phenotypes of liver disease due to chronic hepatitis C virus (HCV) infection show a wide range of variations in terms of histological manifestations and the clinical outcome. Sensing of viral double-stranded RNA (dsRNA) by Toll-like receptor 3 (TLR3) is likely involved in early pathogen detection and the host response to viral infection. This study analyzed epidemiological and clinical data from a total of 137 patients with chronic HCV infection with regard to two polymorphic positions within the TLR3 gene: rs5743305 (T/A) is located within the promoter region and might affect transcriptional activity, rs3775291 (C/T) is a non-synonymous single nucleotide polymorphism (SNP) located within exon 4 and the variant receptor has been shown to be functionally impaired. TLR3 promoter and the exon 4 variations were not found to be associated with TLR3 gene expression in peripheral blood mononuclear cells (PBMCs). In the liver, however, a tendency of higher TLR3 gene expression was found for exon 4 TT genotypes. Both variations were not found to be associated with clinical parameters of chronic disease. On the other hand, an analysis of the TLR3 exon 4 genotype distribution with respect to HCV subtype revealed an absence of TT genotype among HCV subtype 1a infected individuals. This study thus failed to reveal any association of the two SNPs under investigation with clinical parameters of chronic hepatitis C. However, data argue for a functional relevance of the exon 4 SNP in terms of conferring a different susceptibility towards HCV subtype infection.
Interferon regulatory factor-1 (IRF-1), a transcription regulator involved both in inducing and in mediating the effects of interferon, is encoded by a highly polymorphic gene in different ethnic populations. Some of these genetic variations have been described to be associated to disease traits in hepatitis C virus and in human immunodeficiency virus infection, including one single-nucleotide polymorphism rs2549009 within the promoter region. This study aimed at investigating the functional relevance of rs2549009 on IRF-1 transcriptional activity in peripheral blood mononuclear cells in its natural genomic environment. Haplotype-specific chromatin immunoprecipitation using antibodies directed against both the transcriptionally inactive and active RNA polymerase II (RNAPII) and allele-specific transcript quantification techniques were applied to ex vivo-derived samples from healthy heterozygous donors. Inactive serine 5 phosphorylated RNAPII was found to be preferentially bound to the rs2549009 A allele in all donors investigated. Active serine 2 phosphorylated (ser2-P) RNAPII, in contrast, was found to be precipitable, depending on the donor, preferentially either with the A or the G promoter variants or without any preference. The ratio of rs2549009 A/G promoter variants engaged by ser2-P RNAPII was closely related to the relative frequency of the respective IRF-1 transcripts, and relative allelic expression was found to be associated to total IRF-1 gene expression. These results provide evidence for a bidirectional IRF-1 gene expression imbalance that appears not to be solely controlled by rs2549009 in cis and may rely on a yet unidentified variant or haplotype or on environmental control in trans.
Screening of an Antarctic soil functional fosmid metagenomic library identified a novel bacterial gene, homologous to known Water Hypersensitivity (WHy) domains. The WHy domain is a typical component of Late Embryogenesis Abundant (LEA) proteins which occurs widely in both prokaryotes and in plant eukaryotes and are expressed under various stress conditions [1]. A phylogenetic analysis of multiple WHy homologues from different species suggested that the ancestral origin of this protein gene lies within the ancient archaea [1]. Our previous studies have shown that this bacterial protein elicits significant protection against freeze and cold stress in recombinant E. coli [2]. Expression of the WHy gene in Arabidopsis resulted in a wide range of statistically significant stress-tolerant phenotypic properties. These included an increase of up to 6-fold higher germination efficiency of transgenic recombinant seeds compared to the WT, and a 100 % survival rate of WHy gene-expressing plants compared to 0 % survival of adult WT plants after freeze shock. Similar improvements in survival rates were observed for recombinant plants in drought stress experiments. References Mertens J, Aliyu H, Cowan DA (2018). Applied and environmental microbiology, AEM-00539. Anderson D, Ferreras E, Trindade M, Cowan D (2015). FEMS Microbiology Letters, 362(15):fnv110.
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