Reviews & Analysis

The year 2014 marks the 50th anniversary of the discovery of protein acetylation. In this Timeline article, Verdin and Ott discuss the identification of this modification, of its regulatory enzymes and of the roles of acetylation in transcription and other cellular processes, and provide an outlook on the future of the field.

The subcellular localization of mRNAs enables the spatial regulation of protein translation and generates functional and structural asymmetries in cells. New imaging (and other) techniques for tracking single-mRNA dynamics have unravelled mechanisms of mRNA movements and localization patterns in various cell types.

Post-translational modification of proteins by NEDD8 has been mainly characterized in terms of the cullin–RING E3 ligase family. However, recent studies have indicated that there might be non-cullin neddylation targets that require further verification.

Intrinsically disordered proteins (IDPs) are key components of the cellular signalling machinery. Their flexible conformation enables them to interact with different partners and to participate in the assembly of signalling complexes and membrane-less organelles; this leads to different cellular outcomes. Post-translational modification of IDPs and alternative splicing add complexity to regulatory networks.

Lys and Arg methylation on non-histone proteins regulates various signalling pathways, and its crosstalk with other post-translational modifications and with histone methylation affects cellular processes such as transcription and DNA damage repair. Advances in proteomics now allow us to decode the methylproteome and elucidate its functions.

Faithful chromosome segregation during mitosis depends on the bi-oriented attachment of chromosomes to spindle microtubules through their kinetochores. The precise regulation of kinetochore–microtubule attachment that ensures error-free mitosis may be explained by homeostatic principles involving receptors, a core control network, effectors and feedback control.

New insights into how iron–sulphur (Fe–S) clusters are incorporated into proteins, particularly the discovery of a role for Leu-Tyr-Arg motifs in Fe–S recipient proteins, are shedding light on the fundamental roles of Fe–S proteins in mammalian cells.

The extracellular matrix (ECM) regulates many cellular functions, and its remodelling by enzymes such as metalloproteinases has a crucial role during development, as exemplified by intestinal, lung, mammary gland and submandibular gland morphogenesis. ECM structure and composition are important therapeutic targets, as their dysregulation contributes to conditions such as fibrosis and invasive cancer.

The molecules that are associated with the extracellular matrix (ECM) in different tissues, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled, determine the structure and the organization of the ECM. The resultant biochemical and biophysical properties of the ECM dictate its tissue-specific functions.

The form of vertebrates is shaped by the sensing and relaying of mechanical forces that are applied between cells and their microenvironment. Mechanobiology has emerged as a field of research dedicated to studying these forces and their communication through signalling processes, which are collectively known as mechanotransduction.

The physical properties of the extracellular environment — in terms of confinement, rigidity, surface topology and adhesion-ligand density — can have profound effects on the migration strategy and migration velocity of cells in differentin vivocontexts.

Somite formation relies on a molecular oscillator, the segmentation clock, which leads to oscillatory gene expression in the presomitic mesoderm; this is converted into the periodic generation of segments in response to signalling gradients referred to as the wavefront. Recent studies provide insights into the molecular mechanisms behind this intricate developmental system.

In soft connective tissues at the steady state, cells continually read environmental cues and respond to promote mechanical homeostasis of the extracellular matrix and ensure cellular and tissue health. Progress has been made into our understanding of the molecular, cellular and tissue scale responses to mechanical load that promote mechanical homeostasis.

Recent data suggest that histone modifications have a direct effect on nucleosomal architecture. Acetylation, methylation, phosphorylation and citrullination of the histone core may influence chromatin structure by affecting histone–histone and histone–DNA interactions, as well as the binding of histones to chaperones.

It is unclear how totipotent embryonic cells acquire their fate and what role chromatin dynamics have in this process. Technological advances in studying single cells have begun to improve our understanding of the mechanisms underlying lineage allocation and cell plasticity in early mammalian development.

The mechanisms underlying spindle checkpoint signalling at the kinetochore, which ensures faithful chromosome segregation during cell division, are being unravelled. They indicate that the checkpoint response is graded rather than switch-like (completely on or off) as traditionally thought, and provide insights for the treatment of cancers in which the checkpoint is bypassed.

Recent advances in three-dimensional (3D) culture techniques have increased our understanding of the cellular mechanisms that drive epithelial tissue development, the genetic regulation of cell behaviours in epithelial tissues and the role of microenvironmental factors in normal development and disease. 3D culture can be used to build complex organs and to advance therapeutic approaches.

Mitochondria contain a genome that is inherited maternally; this complicates their segregation during cell division, oogenesis and development. Mechanisms that ensure mitochondrial integrity include fusion and fission processes, organelle transport, mitophagy and genetic selection. Defects in these processes can lead to cell and tissue pathologies.

The actin capping activity of capping protein (CP) is indirectly regulated by competing with other factors for filament binding, or directly by factors that bind CP and sterically inhibit its interactions with filaments. Other proteins interact with CP through their 'capping protein interaction' (CPI) motif and modulate its activity via allosteric effects.

Recent studies suggest that mechanisms ofde novo lumen formation in different systems — such as the zebrafish vasculature, C. elegans excretory cells, the D. melanogastertrachea and three-dimensional cultures of endothelial and MDCK cells — share some common features. They all involve expansion of the apical plasma membrane, vesicle transport and regulation of the microtubule and actin cytoskeletons.