Review Articles

Translation is controlled mainly during its initiation. Recent studies in yeast and mammals provide new insights into the mechanism of translation initiation regulation in health and in various diseases, and open avenues for the development of innovative therapies targeting the translation machinery.

Lysosomes orchestrate key cellular functions such as nutrient sensing, degradation of macromolecules and stress adaptation. This Review discusses the integration of signalling pathways at the lysosome and highlights the interaction of lysosomes with other organelles and mechanisms that ensure lysosome homeostasis.

Intrinsically disordered regions of proteins lack a defined 3D structure and exist in a collection of interconverting conformations. Recent work is shedding light on how — through their conformational malleability and adaptability — intrinsically disordered regions extend the repertoire of macromolecular interactions in the cell and contribute to key cellular functions.

The regenerative abilities of mammalian hair follicles are facilitated by the proliferation of hair follicle stem cells (HFSCs), which reside in specialized niches within the skin. Recent studies shed light on how local signals and systemic inputs from the body and the environment regulate HFSC function.

Human endogenous retroviruses (HERVs) are relics of ancient retroviral infections, which provide coding and non-coding sequences to the human genome. Emerging evidence reveals how HERVs contribute to immune responses and embryogenesis and how infections and mutations can dysregulate them and contribute to neurodegeneration, inflammation and oncogenesis.

Eukaryotic membrane fusion is hindered by energy barriers and often requires soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) to facilitate formation of a fusion pore. Recent studies describe SNARE activity along the fusion pathway and shed light on the regulation of SNARE complex assembly.

Targeted editing of mitochondrial and chloroplast genomes has therapeutic, agricultural and environmental potential, but it is challenging owing to inability of transfecting (guide) RNA into the organelles. Recent designs of protein-only, programmable base editors open promising avenues for organellar DNA editing in cell lines, animals and plants.

A unique feature of mitochondrial DNA function is the coupling of initiation of transcription with that of replication. Tan et al. discuss the choice between initiation of either process, and how mitochondrial DNA packaging into nucleoids controls its accessibility and function in human cells.

Iron homeostasis in animals is tightly controlled, and numerous cellular pathways regulate iron uptake, storage, metabolism and secretion. Recent findings provide new insights into the sensory systems that fine-tune iron homeostasis and explain how cellular and systemic iron fluxes intersect.

Antioxidants modulate the levels of reactive oxygen species to allow their physiological roles whilst minimizing the oxidative damage and pathology. The roles and mechanisms of antioxidants are complex and context-dependent, necessitating better understanding of their actions in vivo and warranting caution with their use as therapeutic agents.

Forkhead box (FOXO) transcription factors are important mediators of cell stress responses, generally considered to preserve homeostasis and counteract ageing. However, FOXO-mediated mechanisms can also support the survival of cancer and other dysfunctional cells, thereby complicating the link between FOXOs and lifespan extension.

In this Review, the authors outline the thermodynamic and kinetic principles of protein misfolding and amyloid formation. Mechanisms of toxicity are discussed, focusing on the effect of amyloid interactions with cellular components, and the association of aggregation with healthy ageing and pathology.

YAP and TAZ are transcription coactivators with key roles in development and regeneration as well as in cancer. Many of these roles are executed by YAP/TAZ activation in stem cells. This Review discusses how YAP/TAZ regulate stem cell biology, and considers potential applications of modulating YAP/TAZ in regenerative medicine and cancer therapy.

Mechanistic target of rapamycin mTOR complex 1 (mTORC1) is a central regulator of cellular metabolism. Recent studies of the molecular architecture of mTORC1 shed new light on its physiological functions and on the consequences of their dysregulation in cancer, type 2 diabetes and neurodegeneration.

The transforming growth factor-β (TGFβ) family of cytokines act in development and in homeostasis to regulate cell fate decisions. New insights reveal that small perturbations in TGFβ signalling are tolerated during early development but lead to cancer or congenital disorders at later stages.

The receptor-interacting serine/threonine-protein kinase 1 functions as a molecular switch to control cell survival, inflammation and cell death. Recent mechanistic studies shed light on the catalytic and non-catalytic roles and on the context-dependent functions of receptor-interacting serine/threonine-protein kinase 1 in health and disease.

Endoplasmic reticulum-associated protein degradation (ERAD) enables removal of aberrant or surplus proteins from the ER. ERAD represents a collection of independent processes exhibiting distinct yet overlapping selectivity for a wide range of substrates, enabling efficient quality control of membrane and secretory proteins.

Heat shock protein 90 (HSP90) is a chaperone that facilitates protein folding. In diseased cells, HSP90 and its co-chaperones form oligomers, known as epichaperomes, that confer aberrant scaffolding and holding functions onto the chaperone.

Vascular endothelial growth factor A (VEGFA) is an important regulator of angiogenesis. Increasing knowledge of its role in pathophysiology has culminated in the wide use of anti-VEGFA agents in oncology and in the treatment of neovascular eye disorders, and has opened avenues for promoting tissue vascularization in regenerative medicine.

All aspects of gene regulation involve RNA helicases, which bind or remodel RNA and RNA–protein complexes. Recent data establish a link between helicase structure, mechanism of function and biological roles, including in diseases such as cancer and neurological disorders, with implications for the design of small-molecule inhibitors.