Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.

/pdf/the-emerging-role-of-chromatin-remodelers-in-2cbar8zikx.pdf

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective.

Coupled transcription-translation (CTT) is a hallmark of prokaryotic gene expression. CTT occurs when ribosomes associate with and initiate translation of mRNAs whose transcription has not yet concluded, therefore forming "RNAP.mRNA.ribosome" complexes. CTT is a well-documented phenomenon that is involved in important gene regulation processes, such as attenuation and operon polarity. Despite the progress in our understanding of the cellular signals that coordinate CTT, certain aspects of its molecular architecture remain controversial. Additionally, new information on the spatial segregation between the transcriptional and the translational machineries in certain species, and on the capability of certain mRNAs to localize translation-independently, questions the unanimous occurrence of CTT. Furthermore, studies where transcription and translation were artificially uncoupled showed that transcription elongation can proceed in a translation-independent manner. Here, we review studies supporting the occurrence of CTT and findings questioning its extent, as well as discuss mechanisms that may explain both coupling and uncoupling, e.g., chromosome relocation and the involvement of cis- or trans-acting elements, such as small RNAs and RNA-binding proteins. These mechanisms impact RNA localization, stability, and translation. Understanding the two options by which genes can be expressed and their consequences should shed light on a new layer of control of bacterial transcripts fate.

/pdf/coupled-transcription-translation-in-prokaryotes-an-old-57m7u6uikw.pdf

Coupled Transcription-Translation in Prokaryotes: An Old Couple With New Surprises.

The spatial and temporal coordination of protein transport is an essential cornerstone of the bacterial adaptation to different environmental conditions. By adjusting the protein composition of extra-cytosolic compartments, like the inner and outer membranes or the periplasmic space, protein transport mechanisms help shaping protein homeostasis in response to various metabolic cues. The universally conserved SecYEG translocon acts at the center of bacterial protein transport and mediates the translocation of newly synthesized proteins into and across the cytoplasmic membrane. The ability of the SecYEG translocon to transport an enormous variety of different substrates is in part determined by its ability to interact with multiple targeting factors, chaperones and accessory proteins. These interactions are crucial for the assisted passage of newly synthesized proteins from the cytosol into the different bacterial compartments. In this review, we summarize the current knowledge about SecYEG-mediated protein transport, primarily in the model organism Escherichia coli, and describe the dynamic interaction of the SecYEG translocon with its multiple partner proteins. We furthermore highlight how protein transport is regulated and explore recent developments in using the SecYEG translocon as an antimicrobial target.

/pdf/the-dynamic-secyeg-translocon-3oh69sriec.pdf

The Dynamic SecYEG Translocon.

The large abundance of small open reading frames (smORFs) in prokaryotic and eukaryotic genomes and the plethora of smORF-encoded small proteins became only apparent with the constant advancements in bioinformatic, genomic, proteomic, and biochemical tools. Small proteins are typically defined as proteins of < 50 amino acids in prokaryotes and of less than 100 amino acids in eukaryotes, and their importance for cell physiology and cellular adaptation is only beginning to emerge. In contrast to antimicrobial peptides, which are secreted by prokaryotic and eukaryotic cells for combatting pathogens and competitors, small proteins act within the producing cell mainly by stabilizing protein assemblies and by modifying the activity of larger proteins. Production of small proteins is frequently linked to stress conditions or environmental changes, and therefore, cells seem to use small proteins as intracellular modifiers for adjusting cell metabolism to different intra- and extracellular cues. However, the size of small proteins imposes a major challenge for the cellular machinery required for protein folding and intracellular trafficking and recent data indicate that small proteins can engage distinct trafficking pathways. In the current review, we describe the diversity of small proteins in prokaryotes and eukaryotes, highlight distinct and common features, and illustrate how they are handled by the protein trafficking machineries in prokaryotic and eukaryotic cells. Finally, we also discuss future topics of research on this fascinating but largely unexplored group of proteins.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/febs.15845

The largely unexplored biology of small proteins in pro- and eukaryotes.

In recent years there has been increased appreciation that a whole category of proteins-small proteins of around 50 amino acids or fewer in length-have been missed by annotation as well as by genetic and biochemical assays. With the increased recognition that small proteins are stable within cells and have regulatory functions, there has been intensified study of these proteins. As a result, important questions about small proteins in bacteria and archaea are coming to the fore. Here, we give an overview of these questions, the initial answers, and the approaches needed to address the questions more fully. More detailed discussions of how small proteins can be identified by ribosome profiling and mass spectrometry approaches are provided by two accompanying reviews. We are excited by the prospects of new insights and possibly therapeutic approaches coming from this emerging field.

Small Proteins; Big Questions.

Small membrane proteins represent a largely unexplored yet abundant class of proteins in pro- and eukaryotes. They essentially consist of a single transmembrane domain and are associated with stress response mechanisms in bacteria. How these proteins are inserted into the bacterial membrane is unknown. Our study revealed that in Escherichia coli, the 27-amino-acid-long model protein YohP is recognized by the signal recognition particle (SRP), as indicated by in vivo and in vitro site-directed cross-linking. Cross-links to SRP were also observed for a second small membrane protein, the 33-amino-acid-long YkgR. However, in contrast to the canonical cotranslational recognition by SRP, SRP was found to bind to YohP posttranslationally. In vitro protein transport assays in the presence of a SecY inhibitor and proteoliposome studies demonstrated that SRP and its receptor FtsY are essential for the posttranslational membrane insertion of YohP by either the SecYEG translocon or by the YidC insertase. Furthermore, our data showed that the yohP mRNA localized preferentially and translation-independently to the bacterial membrane in vivo. In summary, our data revealed that YohP engages an unique SRP-dependent posttranslational insertion pathway that is likely preceded by an mRNA targeting step. This further highlights the enormous plasticity of bacterial protein transport machineries.

/pdf/posttranslational-insertion-of-small-membrane-proteins-by-1n6xa14jn8.pdf

Princess M. Walker

Papers

Posttranslational insertion of small membrane proteins by the bacterial signal recognition particle.