Showing papers in "Nature Reviews Molecular Cell Biology in 2017"
TL;DR: This work has shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates and has proposed a physical framework for this organizing principle.
Abstract: In addition to membrane-bound organelles, eukaryotic cells feature various membraneless compartments, including the centrosome, the nucleolus and various granules. Many of these compartments form through liquid–liquid phase separation, and the principles, mechanisms and regulation of their assembly as well as their cellular functions are now beginning to emerge. Biomolecular condensates are micron-scale compartments in eukaryotic cells that lack surrounding membranes but function to concentrate proteins and nucleic acids. These condensates are involved in diverse processes, including RNA metabolism, ribosome biogenesis, the DNA damage response and signal transduction. Recent studies have shown that liquid–liquid phase separation driven by multivalent macromolecular interactions is an important organizing principle for biomolecular condensates. With this physical framework, it is now possible to explain how the assembly, composition, physical properties and biochemical and cellular functions of these important structures are regulated.
3,294 citations
TL;DR: N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses.
Abstract: The recent discovery of reversible mRNA methylation has opened a new realm of post-transcriptional gene regulation in eukaryotes. The identification and functional characterization of proteins that specifically recognize RNA N6-methyladenosine (m6A) unveiled it as a modification that cells utilize to accelerate mRNA metabolism and translation. N6-adenosine methylation directs mRNAs to distinct fates by grouping them for differential processing, translation and decay in processes such as cell differentiation, embryonic development and stress responses. Other mRNA modifications, including N1-methyladenosine (m1A), 5-methylcytosine (m5C) and pseudouridine, together with m6A form the epitranscriptome and collectively code a new layer of information that controls protein synthesis.
1,369 citations
TL;DR: The membrane raft hypothesis formalized a physicochemical principle for a subtype of lateral membrane heterogeneity, in which the preferential associations between cholesterol and saturated lipids drive the formation of relatively packed membrane domains that selectively recruit certain lipids and proteins.
Abstract: Cellular plasma membranes are laterally heterogeneous, featuring a variety of distinct subcompartments that differ in their biophysical properties and composition. A large number of studies have focused on understanding the basis for this heterogeneity and its physiological relevance. The membrane raft hypothesis formalized a physicochemical principle for a subtype of such lateral membrane heterogeneity, in which the preferential associations between cholesterol and saturated lipids drive the formation of relatively packed (or ordered) membrane domains that selectively recruit certain lipids and proteins. Recent studies have yielded new insights into this mechanism and its relevance in vivo, owing primarily to the development of improved biochemical and biophysical technologies.
1,349 citations
TL;DR: This Review discusses the most recent findings regarding the relative involvement of the different NHEJ proteins in the repair of various DNA-end configurations and the relevance of these different pathways to human disease.
Abstract: DNA double-strand breaks (DSBs) are the most dangerous type of DNA damage because they can result in the loss of large chromosomal regions. In all mammalian cells, DSBs that occur throughout the cell cycle are repaired predominantly by the non-homologous DNA end joining (NHEJ) pathway. Defects in NHEJ result in sensitivity to ionizing radiation and the ablation of lymphocytes. The NHEJ pathway utilizes proteins that recognize, resect, polymerize and ligate the DNA ends in a flexible manner. This flexibility permits NHEJ to function on a wide range of DNA-end configurations, with the resulting repaired DNA junctions often containing mutations. In this Review, we discuss the most recent findings regarding the relative involvement of the different NHEJ proteins in the repair of various DNA-end configurations. We also discuss the shunting of DNA-end repair to the auxiliary pathways of alternative end joining (a-EJ) or single-strand annealing (SSA) and the relevance of these different pathways to human disease.
1,061 citations
TL;DR: Investigating ciliopathies has helped to understand the molecular mechanisms by which the cilium-associated basal body functions in early ciliogenesis, as well as how the transition zone functions in ciliary gating, and how intraflagellar transport enables cargo trafficking and signalling.
Abstract: Motile and non-motile (primary) cilia are nearly ubiquitous cellular organelles. The dysfunction of cilia causes diseases known as ciliopathies. The number of reported ciliopathies (currently 35) is increasing, as is the number of established (187) and candidate (241) ciliopathy-associated genes. The characterization of ciliopathy-associated proteins and phenotypes has improved our knowledge of ciliary functions. In particular, investigating ciliopathies has helped us to understand the molecular mechanisms by which the cilium-associated basal body functions in early ciliogenesis, as well as how the transition zone functions in ciliary gating, and how intraflagellar transport enables cargo trafficking and signalling. Both basic biological and clinical studies are uncovering novel ciliopathies and the ciliary proteins involved. The assignment of these proteins to different ciliary structures, processes and ciliopathy subclasses (first order and second order) provides insights into how this versatile organelle is built, compartmentalized and functions in diverse ways that are essential for human health.
1,017 citations
TL;DR: Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
Abstract: The heat shock protein 90 (HSP90) chaperone machinery is a key regulator of proteostasis under both physiological and stress conditions in eukaryotic cells. As HSP90 has several hundred protein substrates (or 'clients'), it is involved in many cellular processes beyond protein folding, which include DNA repair, development, the immune response and neurodegenerative disease. A large number of co-chaperones interact with HSP90 and regulate the ATPase-associated conformational changes of the HSP90 dimer that occur during the processing of clients. Recent progress has allowed the interactions of clients with HSP90 and its co-chaperones to be defined. Owing to the importance of HSP90 in the regulation of many cellular proteins, it has become a promising drug target for the treatment of several diseases, which include cancer and diseases associated with protein misfolding.
1,016 citations
TL;DR: Fundamental insights into the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.
Abstract: Stem cells and their local microenvironment, or niche, communicate through mechanical cues to regulate cell fate and cell behaviour and to guide developmental processes. During embryonic development, mechanical forces are involved in patterning and organogenesis. The physical environment of pluripotent stem cells regulates their self-renewal and differentiation. Mechanical and physical cues are also important in adult tissues, where adult stem cells require physical interactions with the extracellular matrix to maintain their potency. In vitro, synthetic models of the stem cell niche can be used to precisely control and manipulate the biophysical and biochemical properties of the stem cell microenvironment and to examine how the mode and magnitude of mechanical cues, such as matrix stiffness or applied forces, direct stem cell differentiation and function. Fundamental insights into the mechanobiology of stem cells also inform the design of artificial niches to support stem cells for regenerative therapies.
939 citations
TL;DR: The roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-stranded break repair and the stabilization of replication forks, and in modulating chromatin structure are discussed.
Abstract: Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers. Understanding the role of PARP1 in maintaining genome integrity is not only important for the design of novel chemotherapeutic agents, but is also crucial for gaining insights into the mechanisms of chemoresistance in cancer cells. In this Review, we discuss the roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-strand break repair and the stabilization of replication forks, and in modulating chromatin structure.
928 citations
TL;DR: This work has shown that coordinated splicing networks regulate tissue and organ development, and that alternative splicing has important physiological functions in different developmental processes in humans.
Abstract: Alternative splicing of eukaryotic transcripts is a mechanism that enables cells to generate vast protein diversity from a limited number of genes. The mechanisms and outcomes of alternative splicing of individual transcripts are relatively well understood, and recent efforts have been directed towards studying splicing networks. It has become apparent that coordinated splicing networks regulate tissue and organ development, and that alternative splicing has important physiological functions in different developmental processes in humans.
806 citations
TL;DR: YAP and TAZ mechanotransduction is critical for driving stem cell behaviour and regeneration, and it sheds new light on the mechanisms by which aberrant cell mechanics is instrumental for the onset of multiple diseases, such as atherosclerosis, fibrosis, pulmonary hypertension, inflammation, muscular dystrophy and cancer.
Abstract: A growing body of evidence suggests that mechanical signals emanating from the cell's microenvironment are fundamental regulators of cell behaviour. Moreover, at the macroscopic scale, the influence of forces, such as the forces generated by blood flow, muscle contraction, gravity and overall tissue rigidity (for example, inside of a tumour lump), is central to our understanding of physiology and disease pathogenesis. Still, how mechanical cues are sensed and transduced at the molecular level to regulate gene expression has long remained enigmatic. The identification of the transcription factors YAP and TAZ as mechanotransducers started to fill this gap. YAP and TAZ read a broad range of mechanical cues, from shear stress to cell shape and extracellular matrix rigidity, and translate them into cell-specific transcriptional programmes. YAP and TAZ mechanotransduction is critical for driving stem cell behaviour and regeneration, and it sheds new light on the mechanisms by which aberrant cell mechanics is instrumental for the onset of multiple diseases, such as atherosclerosis, fibrosis, pulmonary hypertension, inflammation, muscular dystrophy and cancer.
764 citations
TL;DR: The roles of APA in diverse cellular processes, including mRNA metabolism, protein diversification and protein localization, and more generally in gene regulation are discussed, and the molecular mechanisms underlying APA are discussed.
Abstract: Alternative polyadenylation (APA) is an RNA-processing mechanism that generates distinct 3' termini on mRNAs and other RNA polymerase II transcripts. It is widespread across all eukaryotic species and is recognized as a major mechanism of gene regulation. APA exhibits tissue specificity and is important for cell proliferation and differentiation. In this Review, we discuss the roles of APA in diverse cellular processes, including mRNA metabolism, protein diversification and protein localization, and more generally in gene regulation. We also discuss the molecular mechanisms underlying APA, such as variation in the concentration of core processing factors and RNA-binding proteins, as well as transcription-based regulation.
TL;DR: In this Review,luorescence nanoscopy uniquely combines minimally invasive optical access to the internal nanoscale structure and dynamics of cells and tissues with molecular detection specificity and the labelling of individual molecules to enable their visualization has emerged as a central challenge.
Abstract: Fluorescence nanoscopy uniquely combines minimally invasive optical access to the internal nanoscale structure and dynamics of cells and tissues with molecular detection specificity. While the basic physical principles of 'super-resolution' imaging were discovered in the 1990s, with initial experimental demonstrations following in 2000, the broad application of super-resolution imaging to address cell-biological questions has only more recently emerged. Nanoscopy approaches have begun to facilitate discoveries in cell biology and to add new knowledge. One current direction for method improvement is the ambition to quantitatively account for each molecule under investigation and assess true molecular colocalization patterns via multi-colour analyses. In pursuing this goal, the labelling of individual molecules to enable their visualization has emerged as a central challenge. Extending nanoscale imaging into (sliced) tissue and whole-animal contexts is a further goal. In this Review we describe the successes to date and discuss current obstacles and possibilities for further development.
TL;DR: The 'hourglass' model of remodeller function is proposed, in which each remodeller subfamily utilizes diverse specialized proteins and protein domains to assist in nucleosomes targeting or to differentially detect nucleosome epitopes.
Abstract: Cells utilize diverse ATP-dependent nucleosome-remodelling complexes to carry out histone sliding, ejection or the incorporation of histone variants, suggesting that different mechanisms of action are used by the various chromatin-remodelling complex subfamilies. However, all chromatin-remodelling complex subfamilies contain an ATPase-translocase 'motor' that translocates DNA from a common location within the nucleosome. In this Review, we discuss (and illustrate with animations) an alternative, unifying mechanism of chromatin remodelling, which is based on the regulation of DNA translocation. We propose the 'hourglass' model of remodeller function, in which each remodeller subfamily utilizes diverse specialized proteins and protein domains to assist in nucleosome targeting or to differentially detect nucleosome epitopes. These modules converge to regulate a common DNA translocation mechanism, to inform the conserved ATPase 'motor' on whether and how to apply DNA translocation, which together achieve the various outcomes of chromatin remodelling: nucleosome assembly, chromatin access and nucleosome editing.
TL;DR: New mechanisms and functions of O-GlcNAcylation that are emerging from these recent developments enable us to begin constructing a unified conceptual framework through which the significance of this modification in cellular and organismal physiology can be understood.
Abstract: O-GlcNAcylation - the attachment of O-linked N-acetylglucosamine (O-GlcNAc) moieties to cytoplasmic, nuclear and mitochondrial proteins - is a post-translational modification that regulates fundamental cellular processes in metazoans. A single pair of enzymes - O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) - controls the dynamic cycling of this protein modification in a nutrient- and stress-responsive manner. Recent years have seen remarkable advances in our understanding of O-GlcNAcylation at levels that range from structural and molecular biology to cell signalling and gene regulation to physiology and disease. New mechanisms and functions of O-GlcNAcylation that are emerging from these recent developments enable us to begin constructing a unified conceptual framework through which the significance of this modification in cellular and organismal physiology can be understood.
TL;DR: The discoveries that have helped to identify the roles of RIPK1, RIPK3, MLKL and other regulators of necroptosis, and how they interact to determine cell fate are outlined.
Abstract: In the early 2000s, receptor-interacting serine/threonine protein kinase 1 (RIPK1), a molecule already recognized as an important regulator of cell survival, inflammation and disease, was attributed an additional function: the regulation of a novel cell death pathway that came to be known as necroptosis. Subsequently, the related kinase RIPK3 and its substrate mixed-lineage kinase domain-like protein (MLKL) were also implicated in the necroptotic pathway, and links between this pathway and apoptosis were established. In this Timeline article, we outline the discoveries that have helped to identify the roles of RIPK1, RIPK3, MLKL and other regulators of necroptosis, and how they interact to determine cell fate.
TL;DR: A model is proposed to explain the present understanding of how differential histone acylation is regulated by the metabolism of the different acyl-CoA forms, which in turn modulates the regulation of gene expression.
Abstract: Eight types of short-chain Lys acylations have recently been identified on histones: propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation. Emerging evidence suggests that these histone modifications affect gene expression and are structurally and functionally different from the widely studied histone Lys acetylation. In this Review, we discuss the regulation of non-acetyl histone acylation by enzymatic and metabolic mechanisms, the acylation 'reader' proteins that mediate the effects of different acylations and their physiological functions, which include signal-dependent gene activation, spermatogenesis, tissue injury and metabolic stress. We propose a model to explain our present understanding of how differential histone acylation is regulated by the metabolism of the different acyl-CoA forms, which in turn modulates the regulation of gene expression.
TL;DR: Advances in the detection and mapping of G4 structures in the human genome and in biologically relevant contexts provide important new insights into the functions of G 4 structures in, for example, the regulation of transcription and genome stability, and uncover their potential relevance for cancer therapy.
Abstract: Single-stranded guanine-rich DNA sequences can fold into four-stranded DNA structures called G-quadruplexes (G4s) that arise from the self-stacking of two or more guanine quartets. There has been considerable recent progress in the detection and mapping of G4 structures in the human genome and in biologically relevant contexts. These advancements, many of which align with predictions made previously in computational studies, provide important new insights into the functions of G4 structures in, for example, the regulation of transcription and genome stability, and uncover their potential relevance for cancer therapy.
TL;DR: This Review examines how the replication stress response that is controlled by the kinase ataxia telangiectasia and Rad3-related (ATR) senses and resolves threats to DNA integrity so that the DNA remains available to read in all of the authors' cells.
Abstract: Replication stress is controlled by the kinase ataxia telangiectasia and Rad3-related (ATR), which senses and resolves threats to DNA integrity. ATR activation is complex and involves a core set of components that recruit ATR to stressed replication forks, stimulate its kinase activity and amplify downstream signalling to maintain the stability of replication forks. One way to preserve a rare book is to lock it away from all potential sources of damage. Of course, an inaccessible book is also of little use, and the paper and ink will continue to degrade with age in any case. Like a book, the information stored in our DNA needs to be read, but it is also subject to continuous assault and therefore needs to be protected. In this Review, we examine how the replication stress response that is controlled by the kinase ataxia telangiectasia and Rad3-related (ATR) senses and resolves threats to DNA integrity so that the DNA remains available to read in all of our cells. We discuss the multiple data that have revealed an elegant yet increasingly complex mechanism of ATR activation. This involves a core set of components that recruit ATR to stressed replication forks, stimulate kinase activity and amplify ATR signalling. We focus on the activities of ATR in the control of cell cycle checkpoints, origin firing and replication fork stability, and on how proper regulation of these processes is crucial to ensure faithful duplication of a challenging genome.
TL;DR: This work has shown that the physical properties of the cellular environment, which include matrix stiffness, topography, geometry and the application of external forces, can alter collective cell behaviours, tissue organization and cell-generated forces.
Abstract: The way in which cells coordinate their behaviours during various biological processes, including morphogenesis, cancer progression and tissue remodelling, largely depends on the mechanical properties of the external environment. In contrast to single cells, collective cell behaviours rely on the cellular interactions not only with the surrounding extracellular matrix but also with neighbouring cells. Collective dynamics is not simply the result of many individually moving blocks. Instead, cells coordinate their movements by actively interacting with each other. These mechanisms are governed by mechanosensitive adhesion complexes at the cell-substrate interface and cell-cell junctions, which respond to but also further transmit physical signals. The mechanosensitivity and mechanotransduction at adhesion complexes are important for regulating tissue cohesiveness and thus are important for collective cell behaviours. Recent studies have shown that the physical properties of the cellular environment, which include matrix stiffness, topography, geometry and the application of external forces, can alter collective cell behaviours, tissue organization and cell-generated forces. On the basis of these findings, we can now start building our understanding of the mechanobiology of collective cell movements that span over multiple length scales from the molecular to the tissue level.
TL;DR: The recent convergence of crystallographic and biochemical in vitro analysis of nucleoporins, the components of the NPC, with cryo-electron microscopic imaging of the entire NPC in situ has provided first pseudo-atomic view of its central core and revealed that an unexpected network of short linear motifs is an important spatial organization principle.
Abstract: Nuclear pore complexes (NPCs) are large protein assemblies that form channels in the nuclear envelope and constitute major routes for nucleocytoplasmic communication. Insights into the complex structure of NPCs provide the basis for understanding their functions and reveal how the dysfunction of their structural components, nucleoporins, contributes to human disease.
TL;DR: Current data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomeres crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.
Abstract: The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.
TL;DR: Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.
Abstract: Planar cell polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted WNT ligands and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.
TL;DR: Bromodomains can be targeted by small-molecule inhibitors, which has stimulated many translational research projects that seek to attenuate the aberrant functions of BRD-containing proteins in disease.
Abstract: Bromodomains (BRDs) are evolutionarily conserved protein-protein interaction modules that are found in a wide range of proteins with diverse catalytic and scaffolding functions and are present in most tissues. BRDs selectively recognize and bind to acetylated Lys residues - particularly in histones - and thereby have important roles in the regulation of gene expression. BRD-containing proteins are frequently dysregulated in cancer, they participate in gene fusions that generate diverse, frequently oncogenic proteins, and many cancer-causing mutations have been mapped to the BRDs themselves. Importantly, BRDs can be targeted by small-molecule inhibitors, which has stimulated many translational research projects that seek to attenuate the aberrant functions of BRD-containing proteins in disease.
TL;DR: It is emphasized how chaperones cooperate in the histone chaperone network and via co-chaperone complexes to match histone supply with demand, thereby promoting proper nucleosome assembly and maintaining epigenetic information by recycling modified histones evicted from chromatin.
Abstract: The association of histones with specific chaperone complexes is important for their folding, oligomerization, post-translational modification, nuclear import, stability, assembly and genomic localization. In this way, the chaperoning of soluble histones is a key determinant of histone availability and fate, which affects all chromosomal processes, including gene expression, chromosome segregation and genome replication and repair. Here, we review the distinct structural and functional properties of the expanding network of histone chaperones. We emphasize how chaperones cooperate in the histone chaperone network and via co-chaperone complexes to match histone supply with demand, thereby promoting proper nucleosome assembly and maintaining epigenetic information by recycling modified histones evicted from chromatin.
TL;DR: How endothelial cells interact with each other and with their tissue environment is illuminated, providing paradigms for vessel type- and organ-specific endothelial differentiation and crucial for understanding how tissues develop and maintain, and how their function becomes abnormal in disease.
Abstract: Blood and lymphatic vessels pervade almost all body tissues and have numerous essential roles in physiology and disease. The inner lining of these networks is formed by a single layer of endothelial cells, which is specialized according to the needs of the tissue that it supplies. Whereas the general mechanisms of blood and lymphatic vessel development are being defined with increasing molecular precision, studies of the processes of endothelial specialization remain mostly descriptive. Recent insights from genetic animal models illuminate how endothelial cells interact with each other and with their tissue environment, providing paradigms for vessel type- and organ-specific endothelial differentiation. Delineating these governing principles will be crucial for understanding how tissues develop and maintain, and how their function becomes abnormal in disease.
TL;DR: Nucleosome dynamics are governed by a complex interplay of histone composition, histone post-translational modifications, nucleosome occupancy and positioning within chromatin, which are influenced by numerous regulatory factors, including general Regulatory factors, chromatin remodellers, chaperones and polymerases.
Abstract: Advances in genomics technology have provided the means to probe myriad chromatin interactions at unprecedented spatial and temporal resolution. This has led to a profound understanding of nucleosome organization within the genome, revealing that nucleosomes are highly dynamic. Nucleosome dynamics are governed by a complex interplay of histone composition, histone post-translational modifications, nucleosome occupancy and positioning within chromatin, which are influenced by numerous regulatory factors, including general regulatory factors, chromatin remodellers, chaperones and polymerases. It is now known that these dynamics regulate diverse cellular processes ranging from gene transcription to DNA replication and repair.
TL;DR: Evidence suggests that context-driven plasticity is conferred by the integration of multiple signals, each serving as an allosteric effector of GR conformation, a key determinant of regulatory complex composition and activity.
Abstract: The glucocorticoid receptor (GR) is a constitutively expressed transcriptional regulatory factor (TRF) that controls many distinct gene networks, each uniquely determined by particular cellular and physiological contexts. The precision of GR-mediated responses seems to depend on combinatorial, context-specific assembly of GR-nucleated transcription regulatory complexes at genomic response elements. In turn, evidence suggests that context-driven plasticity is conferred by the integration of multiple signals, each serving as an allosteric effector of GR conformation, a key determinant of regulatory complex composition and activity. This structural and mechanistic perspective on GR regulatory specificity is likely to extend to other eukaryotic TRFs.
TL;DR: Cellular mechanotransduction, the process of translating mechanical forces into biological signals, is crucial for a wide range of physiological processes and a role for ion channels in sensing mechanical forces has been proposed for decades, but their identity in mammals remained largely elusive until the discovery of Piezos.
Abstract: Cellular mechanotransduction, the process of translating mechanical forces into biological signals, is crucial for a wide range of physiological processes. A role for ion channels in sensing mechanical forces has been proposed for decades, but their identity in mammals remained largely elusive until the discovery of Piezos. Recent research on Piezos has underscored their importance in somatosensation (touch perception, proprioception and pulmonary respiration), red blood cell volume regulation, vascular physiology and various human genetic disorders.
TL;DR: New insights from cryo-electron microscopy and various types of spectroscopy may finally be close to rectifying the mechanism of scission in membrane remodelling and scission.
Abstract: The narrow membrane necks formed during viral, exosomal and intra-endosomal budding from membranes, as well as during cytokinesis and related processes, have interiors that are contiguous with the cytosol. Severing these necks involves action from the opposite face of the membrane as occurs during the well-characterized formation of coated vesicles. This 'reverse' (or 'inverse')-topology membrane scission is carried out by the endosomal sorting complex required for transport (ESCRT) proteins, which form filaments, flat spirals, tubes and conical funnels that are thought to direct membrane remodelling and scission. Their assembly, and their disassembly by the ATPase vacuolar protein sorting-associated 4 (VPS4) have been intensively studied, but the mechanism of scission has been elusive. New insights from cryo-electron microscopy and various types of spectroscopy may finally be close to rectifying this situation.
TL;DR: This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid'lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases.
Abstract: Fatty acids are the most efficient substrates for energy production in vertebrates and are essential components of the lipids that form biological membranes. Synthesis of triacylglycerols from non-esterified free fatty acids (FFAs) combined with triacylglycerol storage represents a highly efficient strategy to stockpile FFAs in cells and prevent FFA-induced lipotoxicity. Although essentially all vertebrate cells have some capacity to store and utilize triacylglycerols, white adipose tissue is by far the largest triacylglycerol depot and is uniquely able to supply FFAs to other tissues. The release of FFAs from triacylglycerols requires their enzymatic hydrolysis by a process called lipolysis. Recent discoveries thoroughly altered and extended our understanding of lipolysis. This Review discusses how cytosolic 'neutral' lipolysis and lipophagy, which utilizes 'acid' lipolysis in lysosomes, degrade cellular triacylglycerols as well as how these pathways communicate, how they affect lipid metabolism and energy homeostasis and how their dysfunction affects the pathogenesis of metabolic diseases. Answers to these questions will likely uncover novel strategies for the treatment of prevalent metabolic diseases.