Reviews & Analysis

Autophagy can serve both tumour-suppressive and tumour-promoting roles, often depending on disease stage and mutational background. Recent findings have advanced our understanding of these seemingly opposing roles of autophagy in cancer cells themselves and in the tumour microenvironment.

Mechanical cues from the extracellular matrix (ECM) regulate cell fate and behaviour through cell–ECM mechanotransduction. Studies of cell–ECM mechanotransduction have largely focused on cells cultured in 2D, and only recently have we begun to unravel how these processes occur in 3D — a context native to many cells in vivo.

CRISPR-based genetic screens are providing new insights into the consequences of deficiencies in DNA damage response and repair pathways. These include insights into the regulation of homologous recombination and of replication stress and their crosstalk with other repair pathways, into novel cancer therapies and into the basis of cancer-drug resistance.

Extracellular vesicles (EVs) have emerged as important players in intercellular communication, carrying proteins, lipids, nucleic acids and various signalling molecules between cells. Unravelling how these different cargoes are sorted into EVs in a regulated and context-specific manner is essential to understanding the specificity of EV-mediated signalling.

Ribosome biogenesis, including ribosomal RNA (rRNA) production, occurs in the nucleolus. Recent studies have revealed how the integrity and copy number of rRNA genes is maintained through a unique recombination system, how rRNA transcription is regulated and how phase separation orchestrates nucleolus function.

Metabolites are generally viewed as intermediates or products of metabolism. However, many metabolites are also signalling molecules that regulate metabolic reactions and other processes in development, homeostasis and disease. As such, metabolites can confer adaptive responses to environmental changes.

The inability of the mammalian central nervous system to functionally regenerate after injury is largely attributable to the limited capacity of injured neurons to regrow axons. In the spinal cord, recent work on the mechanisms restricting axon regrowth suggests new therapeutic avenues to promote functional recovery after damage.

This Consensus Statement addresses the definition, nomenclature and classification of long non-coding RNAs, and provides a shared viewpoint on their features and functions. The authors also discuss research challenges and provide recommendations to advance our understanding of long non-coding RNAs.

The proteins apoptosis regulator BAX (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-2-related ovarian killer protein (BOK), gasdermins and mixed lineage kinase domain-like protein (MLKL) are key executioners of regulated cell death by forming pores across the plasma or mitochondrial membrane. This Review discusses structural rearrangements during activation and oligomerization of these proteins and highlights commonalities and differences of pore formation mechanisms.

Membraneless organelles (MLOs) contribute to intracellular compartmentalization and to various cellular processes. This Review provides a guide to MLOs involved in gene regulation in eukaryotes, discussing their assembly, structure, roles in transcription, RNA processing and translation — particularly in stress conditions — and their disease relevance.

The genome contains various non-coding regulatory elements, including silencers of gene expression. Recent progress in the identification and characterization of silencers has considerably deepened our understanding of their function, and has shed light on the potential relevance of targeting silencers in therapy for hereditary diseases.

AMP-activated protein kinase (AMPK) is a cellular energy sensor canonically activated by increases in AMP/ADP to ATP ratios. Recent advances revealed several non-canonical pathways for AMPK activation, including roles of calcium, nutrients and metabolites, as well as DNA and lysosome damage, providing novel insights into the pathology of AMPK in cancer, metabolic disease, fibrosis and inflammation.

Selective autophagy engages several cargo receptors that target specific, potentially toxic, content (damaged organelles, protein aggregates, pathogens) for lysosomal degradation. Understanding of the mechanisms governing this process in mammals has expanded in recent years, opening the prospects for enhancing selective autophagy to boost cellular quality control capabilities.

Recent studies have expanded our understanding of the mechanisms and functions of ubiquitylation. Pathogens rewrite ubiquitylation to promote infection through unconventional ubiquitylation involving lipids and sugars, and structural studies have revealed that ubiquitin functions involve elaborate multivalent interactions that regulate transcription or protein degradation.

Alternative splicing substantially contributes to proteomic complexity in multicellular eukaryotes and regulates various physiological and pathological processes, including cell differentiation, neuron self-avoidance, cancer and autism spectrum disorders. Recent advances paved the way to clinical use of alternative splicing-based therapies for hereditary diseases.

Integrator is the only metazoan-specific RNA polymerase II (Pol II)-associated large multisubunit complex. Processing of non-coding RNAs by Integrator is essential for their biogenesis, and, at protein-coding genes, Integrator regulates Pol II promoter-proximal pausing and elongation. Consequently, Integrator has diverse roles in development and tumorigenesis.

Cell competition results in stochastic cell turnover or elimination of less fit cells from a tissue. Although cell competition generally supports tissue development and homeostasis, it can also promote malignant growth and is subverted during ageing. Addressing how cell fitness is determined and sensed is being actively pursued.

Cell–extracellular matrix (ECM) interactions occur at specialized, multi-protein adhesion complexes, with clustered integrins as the predominant ECM receptors. Progress in characterization of adhesion composition, organization and dynamics in response to force has improved understanding of adhesion maturation and turnover and the relationships between adhesion structures and functions.

PIWI-interacting RNAs (piRNAs) are small non-coding RNAs with essential roles in germ line development through silencing of transposable elements and in regulation of protein-coding genes. Recent studies have deepened our understanding of the biogenesis and function of piRNAs and their roles in infertility, cancer and neurological diseases in humans.

Podosomes and invadopodia, collectively called ‘invadosomes’, are actin-based structures that drive proteolytic invasion in various physiologically relevant cell types (including osteoclasts, immune cells, endothelial cells and fibroblasts) and in cancer cells. Recent work has expanded our understanding of the architecture and mechanisms of invadosomes, and has revealed their diverse functions beyond matrix degradation.