The plasma membrane of eukaryotic cells is not a simple sheet of lipids and proteins but is differentiated into subdomains with crucial functions. Caveolae, small pits in the plasma membrane, are the ...most abundant surface subdomains of many mammalian cells. The cellular functions of caveolae have long remained obscure, but a new molecular understanding of caveola formation has led to insights into their workings. Caveolae are formed by the coordinated action of a number of lipid-interacting proteins to produce a microdomain with a specific structure and lipid composition. Caveolae can bud from the plasma membrane to form an endocytic vesicle or can flatten into the membrane to help cells withstand mechanical stress. The role of caveolae as mechanoprotective and signal transduction elements is reviewed in the context of disease conditions associated with caveola dysfunction.
Caveolae: Formation, dynamics, and function Parton, Robert G.; McMahon, Kerrie-Ann; Wu, Yeping
Current opinion in cell biology,
August 2020, 2020-08-00, 20200801, Letnik:
65
Journal Article
Recenzirano
Caveolae are abundant surface pits formed by the assembly of cytoplasmic proteins on a platform generated by caveolin integral membrane proteins and membrane lipids. This membranous assembly can bud ...off into the cell or can be disassembled releasing the cavin proteins into the cytosol. Disassembly can be triggered by increased membrane tension, or by stress stimuli, such as UV. Here, we discuss recent mechanistic studies showing how caveolae are formed and how their unique properties allow them to function as multifunctional protective and signaling structures.
Lipid droplets (LDs) are ubiquitous dynamic organelles that store and supply lipids in all eukaryotic and some prokaryotic cells for energy metabolism, membrane synthesis, and production of essential ...lipid-derived molecules. Interest in the organelle’s cell biology has exponentially increased over the last decade due to the link between LDs and prevalent human diseases and the discovery of new and unexpected functions of LDs. As a result, there has been significant recent progress toward understanding where and how LDs are formed, and the specific lipid pathways that coordinate LD biogenesis.
Hepatitis C virus (HCV) is a single-stranded RNA virus that replicates on endoplasmic reticulum-derived membranes. HCV particle assembly is dependent on the association of core protein with cellular ...lipid droplets (LDs). However, it remains uncertain whether HCV assembly occurs at the LD membrane itself or at closely associated ER membranes. Furthermore, it is not known how the HCV replication complex and progeny genomes physically associate with the presumed sites of virion assembly at or near LDs. Using an unbiased proteomic strategy, we have found that Rab18 interacts with the HCV nonstructural protein NS5A. Rab18 associates with LDs and is believed to promote physical interaction between LDs and ER membranes. Active (GTP-bound) forms of Rab18 bind more strongly to NS5A than a constitutively GDP-bound mutant. NS5A colocalizes with Rab18-positive LDs in HCV-infected cells, and Rab18 appears to promote the physical association of NS5A and other replicase components with LDs. Modulation of Rab18 affects genome replication and possibly also the production of infectious virions. Our results support a model in which specific interactions between viral and cellular proteins may promote the physical interaction between membranous HCV replication foci and lipid droplets.
Caveolae are submicroscopic, plasma membrane pits that are abundant in many mammalian cell types. The past few years have seen a quantum leap in our understanding of the formation, dynamics and ...functions of these enigmatic structures. Caveolae have now emerged as vital plasma membrane sensors that can respond to plasma membrane stresses and remodel the extracellular environment. Caveolae at the plasma membrane can be removed by endocytosis to regulate their surface density or can be disassembled and their structural components degraded. Coat proteins, called cavins, work together with caveolins to regulate the formation of caveolae but also have the potential to dynamically transmit signals that originate in caveolae to various cellular destinations. The importance of caveolae as protective elements in the plasma membrane, and as membrane organizers and sensors, is highlighted by links between caveolae dysfunction and human diseases, including muscular dystrophies and cancer.
G-protein-coupled receptors (GPCRs) are one of the most tractable classes of drug targets. These dynamic proteins can adopt multiple active states that are linked to distinct functional outcomes. ...Such states can be differentially stabilized by ligands interacting with the endogenous agonist-binding orthosteric site and/or by ligands acting via spatially distinct allosteric sites, leading to the phenomena of 'biased agonism' or 'biased modulation'. These paradigms are having a major impact on modern drug discovery, but it is becoming increasingly apparent that 'kinetic context', at the level of both ligand-receptor and receptor-signal pathway kinetics, can have a profound impact on the observation and quantification of these phenomena. The concept of kinetic context thus represents an important new consideration that should be routinely incorporated into contemporary chemical biology and drug discovery studies of GPCR bias and allostery.
Clathrin-independent pathways of endocytosis Mayor, Satyajit; Parton, Robert G; Donaldson, Julie G
Cold Spring Harbor perspectives in biology,
2014-Jun-02, Letnik:
6, Številka:
6
Journal Article
Recenzirano
Odprti dostop
There are many pathways of endocytosis at the cell surface that apparently operate at the same time. With the advent of new molecular genetic and imaging tools, an understanding of the different ways ...by which a cell may endocytose cargo is increasing by leaps and bounds. In this review we explore pathways of endocytosis that occur in the absence of clathrin. These are referred to as clathrin-independent endocytosis (CIE). Here we primarily focus on those pathways that function at the small scale in which some have distinct coats (caveolae) and others function in the absence of specific coated intermediates. We follow the trafficking itineraries of the material endocytosed by these pathways and finally discuss the functional roles that these pathways play in cell and tissue physiology. It is likely that these pathways will play key roles in the regulation of plasma membrane area and tension and also control the availability of membrane during cell migration.
The multiple faces of caveolae Parton, Robert G; Simons, Kai
Nature reviews. Molecular cell biology,
200703, 2007-Mar, 2007-3-00, 20070301, Letnik:
8, Številka:
3
Journal Article
Recenzirano
Caveolae are a highly abundant but enigmatic feature of mammalian cells. They form remarkably stable membrane domains at the plasma membrane but can also function as carriers in the exocytic and ...endocytic pathways. The apparently diverse functions of caveolae, including mechanosensing and lipid regulation, might be linked to their ability to respond to plasma membrane changes, a property that is dependent on their specialized lipid composition and biophysical properties.
Lipid droplets (LDs) are independent organelles that are composed of a lipid ester core and a surface phospholipid monolayer. Recent studies have revealed many new proteins, functions, and phenomena ...associated with LDs. In addition, a number of diseases related to LDs are beginning to be understood at the molecular level. It is now clear that LDs are not an inert store of excess lipids but are dynamically engaged in various cellular functions, some of which are not directly related to lipid metabolism. Compared to conventional membrane organelles, there are still many uncertainties concerning the molecular architecture of LDs and how each function is placed in a structural context. Recent findings and remaining questions are discussed.
Endocytosis is a critical step in the process by which many therapeutic nanomedicines reach their intracellular targets. Our understanding of cellular uptake mechanisms has developed substantially in ...the past five years. However, these advances in cell biology have not fully translated to the nanoscience and therapeutics literature. Misconceptions surrounding the role of different endocytic pathways and how to study these pathways are hindering progress in developing improved nanoparticle therapies. Here, we summarize the latest insights into cellular uptake mechanisms and pathways. We highlight limitations of current systems to study endocytosis, particularly problems with non-specific inhibitors. We also summarize alternative genetic approaches to robustly probe these pathways and discuss the need to understand how cells endocytose particles in vivo. We hope that this critical assessment of the current methods used in studying nanoparticle uptake will guide future studies at the interface of cell biology and nanomedicine.
PDF
