Reviews & Analysis

The Hippo pathway effectors YAP and TAZ regulate normal and tumorigenic organ growth. Recent studies in vitro and in mouse models have shown that these two transcription co-activators can also promote tissue regeneration. This property could be exploited for regenerative medicine, as long as the therapeutic approaches can minimize the potential for cancer development.

Lipid droplets are storage organelles that are important for the regulation of lipid and energy homeostasis, and that serve as buffers against lipotoxicity. Recent studies on the biology of lipid droplets have led to new discoveries about their biogenesis and the complexity of their interactions with other organelles at membrane contact sites.

Our understanding of eukaryotic ribosome assembly has been boosted by recently published cryo-electron microscopy structures of yeast ribosome assembly intermediates. These studies highlight the roles of RNA compaction, checkpoints and proofreading mechanisms of pre-ribosomal particles in the nucleolus, nucleus and cytoplasm.

Non-histone-lysine acetylation affects protein functions by modulating protein stability, interactions, subcellular localization and enzymatic activity and through crosstalk with other post-translational modifications. Acetylation regulates many cellular processes, such as transcription, DNA repair, signal transduction, protein folding and autophagy.

Epithelial–mesenchymal transition (EMT) is crucial for embryogenesis, wound healing and cancer development, and confers greater resistance to cancer therapies. This Review discusses the mechanisms of EMT and its roles in normal and neoplastic tissues, the contribution of cell-intrinsic signals and the microenvironment to inducing EMT, and its effects on the immunobiology of carcinomas.

Epigenetic profiling of germline and zygotic genomes has revealed that a fraction of mammalian genomes do not undergo epigenetic reprogramming during early development, highlighting the importance of epigenetic inheritance in animals. Inheritance of histone modifications, tRNA fragments and microRNAs can affect gene regulation in the offspring; however, in mammals, epigenetic inheritance rarely operates beyond two generations.

Recent data indicate that various transcription factors and RNA polymerase II bind to mitotic chromatin and that thousands of genes remain transcriptionally active in mitosis, contradicting the view that mitotic cells are transcriptionally silenced. These mechanisms provide mitotic transcriptional memory, which allows re-establishment of cell-type-specific gene expression following division.

The activity of many cell type-specific enhancers is regulated by histone deacetylase 3 (HDAC3), which acts in complex with various nuclear receptor co-repressors. HDAC3 is required for many aspects of mammalian development and physiology, including the metabolism of various organs, neuronal- and haematopoietic stem cell fate and function, lung and bone development and intestinal homeostasis.

The distribution of lipids largely depends on their non-vesicular transport by lipid transfer proteins (LTPs). Recent progress in understanding the mechanisms of LTPs, including the appreciation of their widespread activity at membrane contact sites, has provided novel insights into the regulation of lipid trafficking and how it impacts pathophysiology.

Actin and microtubules are essential for key cellular processes, including cell polarization, migration and division. Although their cellular roles are distinct, actin and microtubules also extensively influence each other’s dynamics and organization. This crosstalk encompasses multiple mechanisms and involves various crosslinkers, motors and regulatory proteins as well as mechanical cooperation.

Cellular stress responses primarily serve to rectify stress-associated damage. However, these responses are also coupled with the generation of various signals that are transmitted to the cellular microenvironments or even across tissues. This communication generally supports the maintenance of systemic homeostasis but can also result in pathology.

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. Recent advances in structural biology techniques have provided insight into how amyloid structure may affect the ability of fibrils to spread in a prion-like manner and into their roles in disease.

The cleavage of microRNA (miRNA) precursors by Drosha and Dicer and their loading with Argonaute proteins into RNA-induced silencing complexes are key steps in miRNA biogenesis. Recent studies have clarified the mechanisms of action of these molecular machines and discovered non-canonical miRNA biogenesis pathways.

Endocytosed membrane proteins can either be degraded in the lysosome or recycled back to the membrane. This decision, which has an impact on protein levels, spatial distribution and function, is controlled by recycling machineries at the endosome that recognize and segregate cargo destined for recycling, thereby preventing its degradation.

Uptake of Ca²⁺ ions by mitochondria regulates their functions and serves to buffer Ca²⁺ concentrations to maintain cellular Ca²⁺ homeostasis. Better understanding of the mechanisms, regulation and (patho)physiology of mitochondrial Ca²⁺ influx and efflux offers the possibility to target mitochondrial Ca²⁺ machineries for therapeutic benefit.

MicroRNAs (miRNAs) are key regulators of biological processes. Recent discoveries have expanded our understanding of the control of miRNA function in animals, through alternative processing, miRNA-sequence editing, post-translational modifications of Argonaute proteins, subcellular localization and regulation of miRNA–target interactions.

G protein-coupled receptors (GPCRs) control a plethora of signalling pathways in various contexts. Importantly, a single GPCR can elicit different responses depending on the bound ligand — a phenomenon known as biased agonism. Increasing molecular and structural understanding of biased agonism offers the possibility of designing improved GPCR-targeting drugs.

Metabolomics and lipidomics have enabled the identification of metabolites (such as lipids, amino acids and bile acids) and metabolic pathways that modulate insulin sensitivity both directly and indirectly. Understanding the metabolic adaptations involved in insulin resistance may lead to novel approaches for preventing and treating T2DM.

Protein degradation by the proteasome is crucial for the control of many cellular processes, and defects in proteasomal degradation may lead to cancer and neurodegeneration. TOR complex 1 has a key role in regulating proteasome abundance and assembly and in integrating proteasomal activity with autophagy pathways and, more generally, cell physiology.

Translation deregulation causes many human diseases, which can be broadly categorized into tRNA or ribosomal dysfunction, and deregulation of the integrated stress response or the mTOR pathway. The complexity of the translation process and its cellular contexts could explain the phenotypic variability of these disorders.