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Cell Research Sep 2016Necroptosis and pyroptosis are two forms of programmed cell death with a common feature of plasma membrane rupture. Here we studied the morphology and mechanism of...
Necroptosis and pyroptosis are two forms of programmed cell death with a common feature of plasma membrane rupture. Here we studied the morphology and mechanism of pyroptosis in comparison with necroptosis. Different from necroptosis, pyroptosis undergoes membrane blebbing and produces apoptotic body-like cell protrusions (termed pyroptotic bodies) prior to plasma membrane rupture. The rupture in necroptosis is explosion-like, whereas in pyroptosis it leads to flattening of cells. It is known that the execution of necroptosis is mediated by mixed lineage kinase domain-like (MLKL) oligomers in the plasma membrane, whereas gasdermin-D (GSDMD) mediates pyroptosis after its cleavage by caspase-1 or caspase-11. We show that N-terminal fragment of GSDMD (GSDMD-N) generated by caspase cleavage also forms oligomer and migrates to the plasma membrane to kill cells. Both MLKL and GSDMD-N are lipophilic and the N-terminal sequences of both proteins are important for their oligomerization and plasma membrane translocation. Unlike MLKL which forms channels on the plasma membrane that induces influx of selected ions which osmotically swell the cells to burst, GSDMD-N forms non-selective pores and does not rely on increased osmolarity to disrupt cells. Our study reveals the pore-forming activity of GSDMD and channel-forming activity of MLKL determine different ways of plasma membrane rupture in pyroptosis and necroptosis.
Topics: Amino Acids; Animals; Apoptosis Regulatory Proteins; Cell Line; Cell Membrane; Cell Membrane Permeability; Cell Shape; Humans; Intracellular Signaling Peptides and Proteins; Necrosis; Neoplasm Proteins; Phosphate-Binding Proteins; Protein Kinases; Protein Multimerization; Protein Transport; Pyroptosis; Structure-Activity Relationship
PubMed: 27573174
DOI: 10.1038/cr.2016.100 -
Current Issues in Molecular Biology 2021Alphaherpesviruses are enveloped viruses that enter cells by fusing the viral membrane with a host cell membrane, either within an endocytic vesicle or at the plasma... (Review)
Review
Alphaherpesviruses are enveloped viruses that enter cells by fusing the viral membrane with a host cell membrane, either within an endocytic vesicle or at the plasma membrane. This entry event is mediated by a set of essential entry glycoproteins, including glycoprotein D (gD), gHgL, and gB. gHgL and gB are conserved among herpesviruses, but gD is unique to the alphaherpesviruses and is not encoded by all alphaherpesviruses. gD is a receptor-binding protein, the heterodimer gHgL serves as a fusion regulator, and gB is a class III viral fusion protein. Sequential interactions among these glycoproteins are thought to trigger the virus to fuse at the right place and time. Structural studies of these glycoproteins from multiple alphaherpesviruses has enabled the design and interpretation of functional studies. The structures of gD in a receptor- bound and in an unliganded form reveal a conformational change in the C terminus of the gD ectodomain upon receptor binding that may serve as a signal for fusion. By mapping neutralizing antibodies to the gHgL structures and constructing interspecies chimeric forms of gHgL, interaction sites for both gD and gB on gHgL have been proposed. A comparison of the post fusion structure of gB and an alternative conformation of gB visualized using cryo- electron tomography suggests that gB undergoes substantial refolding to execute membrane fusion. Although these structures have provided excellent insights into the entry mechanism, many questions remain about how these viruses coordinate the interactions and conformational changes required for entry.
Topics: Alphaherpesvirinae; Animals; Cell Membrane; Glycoproteins; Herpesviridae Infections; Humans; Protein Binding; Protein Conformation; Virus Internalization
PubMed: 32764159
DOI: 10.21775/cimb.041.063 -
Human Genetics Aug 2023Exocytosis is the process by which secretory vesicles fuse with the plasma membrane to deliver materials to the cell surface or to release cargoes to the extracellular... (Review)
Review
Exocytosis is the process by which secretory vesicles fuse with the plasma membrane to deliver materials to the cell surface or to release cargoes to the extracellular space. The exocyst-an evolutionarily conserved octameric protein complex-mediates spatiotemporal control of SNARE complex assembly for vesicle fusion and tethering the secretory vesicles to the plasma membrane. The exocyst participates in diverse cellular functions, including protein trafficking to the plasma membrane, membrane extension, cell polarity, neurite outgrowth, ciliogenesis, cytokinesis, cell migration, autophagy, host defense, and tumorigenesis. Exocyst subunits are essential for cell viability; and mutations or variants in several exocyst subunits have been implicated in human diseases, mostly neurodevelopmental disorders and ciliopathies. These conditions often share common features such as developmental delay, intellectual disability, and brain abnormalities. In this review, we summarize the mutations and variants in exocyst subunits that have been linked to disease and discuss the implications of exocyst dysfunction in other disorders.
Topics: Humans; Vesicular Transport Proteins; Cytoplasm; Cell Membrane; Exocytosis; Nervous System Diseases
PubMed: 37085629
DOI: 10.1007/s00439-023-02558-w -
Current Biology : CB Apr 2018Moseley discusses the molecular and mechanical functions of eisosomes - invaginations from the yeast plasma membrane. (Review)
Review
Moseley discusses the molecular and mechanical functions of eisosomes - invaginations from the yeast plasma membrane.
Topics: Cell Membrane; Cell Membrane Structures; Fungi; Phosphoproteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 29689217
DOI: 10.1016/j.cub.2017.11.073 -
Current Biology : CB Apr 2018Biological membranes are thin amphiphilic sheaths, only a few nanometres thick, that define both the boundaries of all cells as well as the diversity of the internal...
Biological membranes are thin amphiphilic sheaths, only a few nanometres thick, that define both the boundaries of all cells as well as the diversity of the internal compartments in eukaryotes. The plasma membrane of a typical prokaryote houses about 20-30% of the cell's expressed proteins, and its lipids account for approximately 10% of the cell's dry mass. The numbers for eukaryotic cells are comparable - the difference in surface area to volume ratio is overall compensated by the eukaryotic endomembrane system. Roughly a fourth of the protein encoded by the human genome carries at least one stretch of sequence predicted to serve as a transmembrane domain. Membranes host substrate exchange, sensing and communication, and life-giving energy conservation via chemiosmotic ATP synthesis.
Topics: Animals; Biological Evolution; Biophysical Phenomena; Cell Fusion; Cell Membrane; Eukaryotic Cells; Evolution, Molecular; Humans; Membrane Proteins; Phospholipids; Phylogeny; Prokaryotic Cells
PubMed: 29689219
DOI: 10.1016/j.cub.2018.01.086 -
Cancer Metastasis Reviews Jun 2020Flotillins 1 and 2 are two ubiquitous, highly conserved homologous proteins that assemble to form heterotetramers at the cytoplasmic face of the plasma membrane in... (Review)
Review
Flotillins 1 and 2 are two ubiquitous, highly conserved homologous proteins that assemble to form heterotetramers at the cytoplasmic face of the plasma membrane in cholesterol- and sphingolipid-enriched domains. Flotillin heterotetramers can assemble into large oligomers to form molecular scaffolds that regulate the clustering of at the plasma membrane and activity of several receptors. Moreover, flotillins are upregulated in many invasive carcinomas and also in sarcoma, and this is associated with poor prognosis and metastasis formation. When upregulated, flotillins promote plasma membrane invagination and induce an endocytic pathway that allows the targeting of cargo proteins in the late endosomal compartment in which flotillins accumulate. These late endosomes are not degradative, and participate in the recycling and secretion of protein cargos. The cargos of this Upregulated Flotillin-Induced Trafficking (UFIT) pathway include molecules involved in signaling, adhesion, and extracellular matrix remodeling, thus favoring the acquisition of an invasive cellular behavior leading to metastasis formation. Thus, flotillin presence from the plasma membrane to the late endosomal compartment influences the activity, and even modifies the trafficking and fate of key protein cargos, favoring the development of diseases, for instance tumors. This review summarizes the current knowledge on flotillins and their role in cancer development focusing on their function in cellular membrane remodeling and vesicular trafficking regulation.
Topics: Animals; Carcinogenesis; Cell Membrane; Humans; Membrane Microdomains; Membrane Proteins; Neoplasms
PubMed: 32297092
DOI: 10.1007/s10555-020-09873-y -
The FEBS Journal Apr 2022Endocytosis is an essential cellular process required for multiple physiological functions, including communication with the extracellular environment, nutrient uptake,... (Review)
Review
Endocytosis is an essential cellular process required for multiple physiological functions, including communication with the extracellular environment, nutrient uptake, and signaling by the cell surface receptors. In a broad sense, endocytosis is accomplished through either constitutive or ligand-induced invagination of the plasma membrane, which results in the formation of the plasma membrane-retrieved endocytic vesicles, which can either be sent for degradation to the lysosomes or recycled back to the PM. This additional function of endocytosis in membrane retrieval has been adopted by excitable cells, such as neurons, for membrane equilibrium maintenance at synapses. The last two decades were especially productive with respect to the identification of brain-specific functions of the endocytic machinery, which additionally include but not limited to regulation of neuronal differentiation and migration, maintenance of neuron morphology and synaptic plasticity, and prevention of neurotoxic aggregates spreading. In this review, we highlight the current knowledge of brain-specific functions of endocytic machinery with a specific focus on three brain cell types, neuronal progenitor cells, neurons, and glial cells.
Topics: Brain; Cell Membrane; Endocytosis; Lysosomes; Synapses
PubMed: 33896112
DOI: 10.1111/febs.15897 -
Journal of Biomedical Science Mar 2016In all eukaryotes, the plasma membrane is critically important as it maintains the architectural integrity of the cell. Proper anchorage and interaction between the... (Review)
Review
In all eukaryotes, the plasma membrane is critically important as it maintains the architectural integrity of the cell. Proper anchorage and interaction between the plasma membrane and the cytoskeleton is critical for normal cellular processes. The ERM (ezrin-radixin-moesin) proteins are a class of highly homologous proteins involved in linking the plasma membrane to the cortical actin cytoskeleton. This review takes a succinct look at the biology of the ERM proteins including their structure and function. Current reports on their regulation that leads to activation and deactivation was examined before taking a look at the different interacting partners. Finally, emerging roles of each of the ERM family members in cancer was highlighted.
Topics: Actin Cytoskeleton; Animals; Cell Membrane; Humans; Neoplasm Proteins; Neoplasms; Phosphoproteins; Sodium-Hydrogen Exchangers
PubMed: 26983550
DOI: 10.1186/s12929-016-0246-3 -
Current Opinion in Cell Biology Feb 2018Actin polymerization provides driving force to aid several types of processes that involve pulling the plasma membrane into the cell, including phagocytosis, cellular... (Review)
Review
Actin polymerization provides driving force to aid several types of processes that involve pulling the plasma membrane into the cell, including phagocytosis, cellular entry of large viruses, and endocytosis. In endocytosis, actin polymerization is especially important under conditions of high membrane tension or high turgor pressure. Recent modeling efforts have shown how actin polymerization can give rise to a distribution of forces around the endocytic site, and explored how these forces affect the shape dynamics; experiments have revealed the structure of the endocytic machinery in increasing detail, and demonstrated key feedback interactions between actin assembly and membrane curvature. Here we provide a perspective on these findings and suggest avenues for future research.
Topics: Actins; Animals; Cell Membrane; Endocytosis; Polymerization; Yeasts
PubMed: 29207306
DOI: 10.1016/j.ceb.2017.11.007 -
Cold Spring Harbor Perspectives in... Jan 2017A variety of intermediate filament (IF) types show intricate association with plasma membrane proteins, including receptors and adhesion molecules. The molecular basis... (Review)
Review
A variety of intermediate filament (IF) types show intricate association with plasma membrane proteins, including receptors and adhesion molecules. The molecular basis of linkage of IFs to desmosomes at sites of cell-cell interaction and hemidesmosomes at sites of cell-matrix adhesion has been elucidated and involves IF-associated proteins. However, IFs also interact with focal adhesions and cell-surface molecules, including dystroglycan. Through such membrane interactions, it is well accepted that IFs play important roles in the establishment and maintenance of tissue integrity. However, by organizing cell-surface complexes, IFs likely regulate, albeit indirectly, signaling pathways that are key to tissue homeostasis and repair.
Topics: Animals; Cell Adhesion; Cell Membrane; Homeostasis; Humans; Intermediate Filaments
PubMed: 28049646
DOI: 10.1101/cshperspect.a025866