The interplay of microbiota and the human host is physiologically crucial in health and diseases. The beneficial effects of lactic acid bacteria (LAB), permanently colonizing the human intestine or transiently obtained from food, have been extensively reported. However, the molecular understanding of how LAB modulate human physiology is still limited. G protein-coupled receptors for hydroxycarboxylic acids ( HCAR ) are regulators of immune functions and energy homeostasis under changing metabolic and dietary conditions. Most mammals have two HCAR (HCA 1 , HCA 2 ) but humans and other hominids contain a third member (HCA 3 ) in their genomes. A plausible hypothesis why HCA 3 function was advantageous in hominid evolution was lacking. Here, we used a combination of evolutionary, analytical and functional methods to unravel the role of HCA 3 in vitro and in vivo . The functional studies included different pharmacological assays, analyses of human monocytes and pharmacokinetic measurements in human. We report the discovery of the interaction of D-phenyllactic acid (D-PLA) and the human host through highly potent activation of HCA 3 . D-PLA is an anti-bacterial metabolite found in high concentrations in LAB-fermented food such as Sauerkraut. We demonstrate that D-PLA from such alimentary sources is well absorbed from the human gut leading to high plasma and urine levels and triggers pertussis toxin-sensitive migration of primary human monocytes in an HCA 3 -dependent manner. We provide evolutionary, analytical and functional evidence supporting the hypothesis that HCA 3 was consolidated in hominids as a new signaling system for LAB-derived metabolites.

Article first published online 23 March 2015.

Canonical microRNAs are excised from their hairpin-shaped precursors by Dicer. In order to find possible exceptions to this rule and to identify additional substrates for Dicer processing we re-evaluate the small RNA sequencing data of the Dicer knockdown experiment in MCF-7 cells orignally published by Friedländer et al. [Nucleic Acids Res. 40: 37-52 (2012)]. While the well-known non-Dicer mir-451 is not sufficiently expressed in these experiments, there are several additional Dicer-independent microRNAs, among them the important tumor supressor mir-663a. We recover previously described examples of non-miRNA Dicer substrates such as tRNA-Gln and several snoRNAs. Interestingly, sdRNAs derived from box C/D snoRNAs are Dicer-independent, while those derived from box H/ACA snoRNAs are often Dicer dependent. Several pol-III transcripts, in particular the vault RNAs and the great ape specific snaRs are processed by Dicer, while the small RNAs originating from Y RNAs seem to be Dicer independent.

The enormous sizes of adhesion G protein-coupled receptors (aGPCRs) go along with complex genomic exon-intron architectures giving rise to multiple mRNA variants. There is a need for a comprehensive catalog of aGPCR variants for proper evaluation of the complex functions of aGPCRs found in structural, in vitro and animal model studies. We used an established bioinformatics pipeline to extract, quantify and visualize mRNA variants of aGPCRs from deeply sequenced transcriptomes. Data analysis showed that aGPCRs have multiple transcription start sites even within introns and that tissue-specific splicing is frequent. On average, 19 significantly expressed transcript variants are derived from a given aGPCR gene. The domain architecture of the N terminus encoded by transcript variants often differs and N termini without or with an incomplete seven-helix transmembrane anchor as well as separate seven-helix transmembrane domains are frequently derived from aGPCR genes. Experimental analyses of selected aGPCR transcript variants revealed marked functional differences. Our analysis has an impact on a rational design of aGPCR constructs for structural analyses and gene-deficient mouse lines and provides new support for independent functions of both, the large N terminus and the transmembrane domain of aGPCRs.

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