Band 2, Heft 6

In this study, we review the current knowledge and recent insights on the role of epigenetic factors in the development of human insulin resistance (IR)- and metabolic syndrome (MS)-related phenotypes, and attempt to lay a framework to consider IR as a potentially reversible incapacity to control metabolic homeostasis that is strongly influenced by the interplay between external and internal cues. We summarize the evidence on how tissue-specific epigenetic markers participate either by activating or repressing the gene expression programs to modulate IR- and MS-associated traits. Some additional data are provided about how the exploration of DNA methylation markers in peripheral blood mononuclear cells potentially offers appealing information about the impact of epigenetics in the pathogenesis of IR. Clues about the relation between IR and impaired intrauterine growth explained by fetal metabolic programming and epigenetic modifications are shown, including novel findings about the impact of histone modifications. For instance, we observed that specific epigenetic factors in genes associated with mitochondrial biogenesis may be associated with birth weight. Furthermore, some prospective ideas about the functional consequences of genetic variation modulated by allele-specific epigenetic markers and its impact on MS susceptibility are also illustrated. Finally, we summarize the current knowledge of epigenetics as the biological rationale for potential therapeutic intervention in IR and MS.

Epigenetic mechanisms have emerged as a central process in learning and memory. Histone modifications and DNA methy­lation are epigenetic events that can mediate gene transcription. Interesting features of these epigenetic changes are their transient and long lasting potential. Recent advances in neuroscience suggest that DNA methylation is both dynamic and stable, mediating the formation and maintenance of memory. In this review, we will further illustrate the recent hypothesis that DNA methylation participates in the transcriptional regulation necessary for memory.

Senescence marker protein 30 (SMP30) is a multifunctional protein involved in cellular Ca 2+ homeostasis and the biosynthesis of ascorbate in nonprimate mammals. The primary structure of the protein is highly conserved among vertebrates, suggesting the existence of a significant physiological function common to all mammals, including primates. Enzymatic activities of SMP30 include aldonolactone and organophosphate hydrolysis. Protective effects against apoptosis and oxidative stress have been reported. X-ray crystallography revealed that SMP30 is a six-bladed β-propeller with structural similarity to paraoxonase 1, another protein with lactonase and organophosphate hydrolase activities. SMP30 has recently been tied to several physiological conditions, including osteoporosis, liver fibrosis, diabetes, and cancer. This review aims to describe the recent advances made toward understanding the connection between molecular structure, enzymatic activity, and physiological function of this highly conserved, multifaceted protein.

Here, we review the history, morphology, immunohistochemical phenotype, and presumptive roles of a new type of interstitial tissue cells, formerly called interstitial Cajal-like cells (ICLC) and by 2010 named ‘telocytes’ (TC). Many different techniques have been used to characterize TC and provide their unequivocal identification: (i) in vitro , cultures and isolated cells; (ii) in situ , fixed specimens examined by light and fluorescence microscopy, transmission (TEM) and scanning electron microscopy, and electron tomography. TEM allowed sure identification and characterization of the most peculiar feature of TC: the long, thin, and convoluted prolongations named ‘telopodes’. An enormous variety of antibodies have been tested, but presently none are reliable to specifically label TC. TC have a mesenchymal origin and are resident connective tissue (stromal) cells. Possible identification with ‘already identified’ stromal cell types (fibroblasts, fibrocytes, fibroblast-like cells, and mesenchymal stromal cells) is discussed. We conclude that in adulthood, most of the TC have the morphology of fibrocytes. Apparently, immunocytochemistry suggests that a variety of TC populations showing different, likely organ-specific, immunophenotypes might exist. Several roles have been hypothesized for TC: mechanical roles, intercellular signaling, guiding and nursing of immature cells during organogenesis, and being themselves a pool of precursors for many of the mesenchyme-derived cells in adulthood; however, none of these roles have been proven yet. On the basis of the available data, we propose TC may be key players in organ regeneration and repair.

The degradation of messenger RNA is of universal importance for controlling gene expression. It directly affects protein synthesis by modulating the amount of mRNA available for translation. Regulation of mRNA decay provides an efficient means to produce just the proteins needed and to rapidly alter patterns of protein synthesis. In bacteria, the half-lives of individual mRNAs can differ by as much as two orders of magnitude, ranging from seconds to an hour. Most of what we know today about the diverse mechanisms of mRNA decay and maturation in prokaryotes comes from studies of the two model organisms Escherichia coli and Bacillus subtilis . Their evolutionary distance provided a large picture of potential pathways and enzymes involved in mRNA turnover. Among them are three ribonucleases, two of which have been discovered only recently, which have a truly general role in the initiating events of mRNA degradation: RNase E, RNase J and RNase Y. Their enzymatic characteristics probably determine the strategies of mRNA metabolism in the organism in which they are present. These ribonucleases are coded, alone or in various combinations, in all prokaryotic genomes, thus reflecting how mRNA turnover has been adapted to different ecological niches throughout evolution.

The twin-arginine translocation (Tat) pathway is found in bacteria, archaea, and plant chloroplasts, where it is dedicated to the transmembrane transport of fully folded proteins. These proteins contain N-terminal signal peptides with a specific Tat-system binding motif that is recognized by the transport machinery. In contrast to other protein transport systems, the Tat system consists of multiple copies of only two or three usually small (∼8–30 kDa) membrane proteins that oligomerize to two large complexes that transiently interact during translocation. Only one of these complexes includes a polytopic membrane protein, TatC. The other complex consists of TatA. Tat systems of plants, proteobacteria, and several other phyla contain a third component, TatB. TatB is evolutionarily and structurally related to TatA and usually forms tight complexes with TatC. Minimal two-component Tat systems lacking TatB are found in many bacterial and archaeal phyla. They consist of a ‘bifunctional’ TatA that also covers TatB functionalities, and a TatC. Recent insights into the structure and interactions of the Tat proteins have various important implications.

Autotransporter proteins are a large family of virulence factors secreted from Gram-negative bacteria by a unique mechanism. First described in the 1980s, these proteins have a C-terminal region that folds into a β-barrel in the bacterial outer membrane. The so-called passenger domain attached to this barrel projects away from the cell surface and may be liberated from the cell by self-cleavage or surface proteases. Although the majority of passenger domains have a similar β-helical structure, they carry a variety of sub­domains, allowing them to carry out widely differing functions related to pathogenesis. Considerable biochemical and structural characterisation of the barrel domain has shown that ‘autotransporters’ in fact require a conserved and essential protein complex in the outer membrane for correct folding. Although the globular domains of this complex projecting into the periplasmic space have also been structurally characterised, the overall secretion pathway of the autotransporters remains highly puzzling. It was presumed for many years that the passenger domain passed through the centre of the barrel domain to reach the cell surface, driven at least in part by folding. This picture is complicated by conflicting data, and there is currently little hard information on the true nature of the secretion intermediates. As well as their medical importance therefore, autotransporters are proving to be an excellent system to study the folding and membrane insertion of outer membrane proteins in general. This review focuses on structural aspects of autotransporters; their many functions in pathogenesis are beyond its scope.

In the adult testis, Sertoli cells (SCs) are the epithelial supporting cells of the seminiferous tubules that provide germ cells (GCs) with the required nutrients and structural and regulatory support to complete spermatogenesis. SCs also form the blood-testis barrier, phagocytose apoptotic spermatocytes and cell debris derived from spermiogenesis, and produce and secrete numerous paracrine and endocrine signals involved in different regulatory processes. In addition to their essential functions in the adult testis, SCs play a pivotal role during testis development. They are the first cells to differentiate in the embryonic XY gonadal primordium and are involved in the regulation of testis-specific differentiation processes, such as prevention of GC entry into meiosis, Leydig and peritubular myoid cell differentiation, and regression of the Müllerian duct, the anlagen of the uterus, oviducts, and the upper part of the vagina. Expression of the Y-linked gene SRY in pre-SCs initiates a genetic cascade that leads to SC differentiation and subsequently to testis development. Since the identification of the SRY gene, many Sertoli-specific transcription factors and signals underlying the molecular mechanisms of early testis differentiation have been identified. Here, we review the state of the art of the molecular interactions that commit the supporting cell lineage of the gonadal primordium to differentiate as SCs and the subsequent Sertoli-specific signaling pathways involved in early testis differentiation.