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Biochimica Et Biophysica Acta.... Oct 2023Gap junctions are specialized regions of the plasma membrane containing clusters of channels that provide for the diffusion of ions and small molecules between adjacent... (Review)
Review
Gap junctions are specialized regions of the plasma membrane containing clusters of channels that provide for the diffusion of ions and small molecules between adjacent cells. A fundamental role of gap junctions is to coordinate the functions of cells in tissues. Cancer pathogenesis is usually associated with loss of intercellular communication mediated by gap junctions, which may affect tumor growth and the response to radio- and chemotherapy. Gap junction channels consist of integral membrane proteins termed connexins. In addition to their canonical roles in cell-cell communication, connexins modulate a range of signal transduction pathways via interactions with proteins such as β-catenin, c-Src, and PTEN. Consequently, connexins can regulate cellular processes such as cell growth, migration, and differentiation through both channel-dependent and independent mechanisms. Gap junctions are dynamic plasma membrane entities, and by modulating the rate at which connexins undergo endocytosis and sorting to lysosomes for degradation, cells can rapidly adjust the level of gap junctions in response to alterations in the intracellular or extracellular milieu. Current experimental evidence indicates that aberrant trafficking of connexins in the endocytic system is intrinsically involved in mediating the loss of gap junctions during carcinogenesis. This review highlights the role played by the endocytic system in controlling connexin degradation, and consequently gap junction levels, and discusses how dysregulation of these processes contributes to the loss of gap junctions during cancer development. We also discuss the therapeutic implications of aberrant endocytic trafficking of connexins in cancer cells.
Topics: Humans; Connexins; Connexin 43; Gap Junctions; Cell Membrane; Neoplasms
PubMed: 37454772
DOI: 10.1016/j.bbadis.2023.166812 -
Current Opinion in Plant Biology Oct 2023To respond to auxin, the chief orchestrator of their multicellularity, plants evolved multiple receptor systems and signal transduction cascades. Despite decades... (Review)
Review
To respond to auxin, the chief orchestrator of their multicellularity, plants evolved multiple receptor systems and signal transduction cascades. Despite decades of research, however, we are still lacking a satisfactory synthesis of various auxin signaling mechanisms. The chief discrepancy and historical controversy of the field is that of rapid and slow auxin effects on plant physiology and development. How is it possible that ions begin to trickle across the plasma membrane as soon as auxin enters the cell, even though the best-characterized transcriptional auxin pathway can take effect only after tens of minutes? Recently, unexpected progress has been made in understanding this and other unknowns of auxin signaling. We provide a perspective on these exciting developments and concepts whose general applicability might have ramifications beyond auxin signaling.
Topics: Cell Membrane; Indoleacetic Acids; Pentaerythritol Tetranitrate; Signal Transduction
PubMed: 37666097
DOI: 10.1016/j.pbi.2023.102443 -
EMBO Reports Nov 2023Compartmentalization by membranes is a common feature of eukaryotic cells and serves to spatiotemporally confine biochemical reactions to control physiology.... (Review)
Review
Compartmentalization by membranes is a common feature of eukaryotic cells and serves to spatiotemporally confine biochemical reactions to control physiology. Membrane-bound organelles such as the endoplasmic reticulum (ER), the Golgi complex, endosomes and lysosomes, and the plasma membrane, continuously exchange material via vesicular carriers. In addition to vesicular trafficking entailing budding, fission, and fusion processes, organelles can form membrane contact sites (MCSs) that enable the nonvesicular exchange of lipids, ions, and metabolites, or the secretion of neurotransmitters via subsequent membrane fusion. Recent data suggest that biomolecule and information transfer via vesicular carriers and via MCSs share common organizational principles and are often mediated by proteins with intrinsically disordered regions (IDRs). Intrinsically disordered proteins (IDPs) can assemble via low-affinity, multivalent interactions to facilitate membrane tethering, deformation, fission, or fusion. Here, we review our current understanding of how IDPs drive the formation of multivalent protein assemblies and protein condensates to orchestrate vesicular and nonvesicular transport with a special focus on presynaptic neurotransmission. We further discuss how dysfunction of IDPs causes disease and outline perspectives for future research.
Topics: Intrinsically Disordered Proteins; Endoplasmic Reticulum; Golgi Apparatus; Cell Membrane; Lysosomes
PubMed: 37680133
DOI: 10.15252/embr.202357758 -
Communications Biology Oct 2023Pyroptosis is a cell death process that causes inflammation and contributes to numerous diseases. Pyroptosis is mediated by caspase-1 family proteases that cleave the...
Pyroptosis is a cell death process that causes inflammation and contributes to numerous diseases. Pyroptosis is mediated by caspase-1 family proteases that cleave the pore-forming protein gasdermin D, causing plasma membrane rupture and release of pathogenic cellular contents. We previously identified muscimol as a small molecule that prevents plasma membrane rupture during pyroptosis via an unidentified mechanism. Here, we show that muscimol has reversible activity to prevent cellular lysis without affecting earlier pyroptotic events. Although muscimol is a well-characterized agonist for neuronal GABA receptors, muscimol protection is not altered by GABA receptor antagonists or recapitulated by other GABA agonists, suggesting that muscimol acts via a novel mechanism. We find that muscimol blocks oligomerization of ninjurin-1, which is required for plasma membrane rupture downstream of gasdermin D pore formation. Our structure-activity relationship studies reveal distinct molecular determinants defining inhibition of pyroptotic lysis compared to GABA binding. In addition, we demonstrate that muscimol reduces lethality during LPS-induced septic shock. Together, these findings demonstrate that ninjurin-1-mediated plasma membrane rupture can be pharmacologically modulated and pave the way toward identification of therapeutic strategies for pathologic conditions associated with pyroptosis.
Topics: Pyroptosis; Muscimol; Gasdermins; Intracellular Signaling Peptides and Proteins; Cell Membrane; Receptors, GABA-A; gamma-Aminobutyric Acid
PubMed: 37798443
DOI: 10.1038/s42003-023-05354-4 -
Biochimica Et Biophysica Acta.... Oct 2023Calcium (Ca)-ATPases are ATP-dependent enzymes that transport Ca ions against their electrochemical gradient playing the fundamental biological function of keeping the... (Review)
Review
Calcium (Ca)-ATPases are ATP-dependent enzymes that transport Ca ions against their electrochemical gradient playing the fundamental biological function of keeping the free cytosolic Ca concentration in the submicromolar range to prevent cytotoxic effects. In plants, type IIB autoinhibited Ca-ATPases (ACAs) are localised both at the plasma membrane and at the endomembranes including endoplasmic reticulum (ER) and tonoplast and their activity is primarily regulated by Ca-dependent mechanisms. Instead, type IIA ER-type Ca-ATPases (ECAs) are present mainly at the ER and Golgi Apparatus membranes and are active at resting Ca. Whereas research in plants has historically focused on the biochemical characterization of these pumps, more recently the attention has been also addressed on the physiological roles played by the different isoforms. This review aims to highlight the main biochemical properties of both type IIB and type IIA Ca pumps and their involvement in the shaping of cellular Ca dynamics induced by different stimuli.
Topics: Adenosine Triphosphatases; Calcium-Transporting ATPases; Plants; Signal Transduction; Cell Membrane
PubMed: 37290725
DOI: 10.1016/j.bbamcr.2023.119508 -
Science Signaling Jun 2024Palmitoylation of intact or cleaved gasdermin D causes plasma membrane pore formation.
Palmitoylation of intact or cleaved gasdermin D causes plasma membrane pore formation.
Topics: Lipoylation; Humans; Cell Membrane; Intracellular Signaling Peptides and Proteins; Animals; Gasdermins; Phosphate-Binding Proteins
PubMed: 38917221
DOI: 10.1126/scisignal.adr1306 -
Science Immunology Jan 2024Pore-forming toxins (PFTs) are the largest class of bacterial toxins and contribute to virulence by triggering host cell death. Vertebrates also express endogenous...
Pore-forming toxins (PFTs) are the largest class of bacterial toxins and contribute to virulence by triggering host cell death. Vertebrates also express endogenous pore-forming proteins that induce cell death as part of host defense. To mitigate damage and promote survival, cells mobilize membrane repair mechanisms to neutralize and counteract pores, but how these pathways are activated is poorly understood. Here, we use a transposon-based gene activation screen to discover pathways that counteract the cytotoxicity of the archetypal PFT α-toxin. We identify the endolysosomal protein LITAF as a mediator of cellular resistance to PFT-induced cell death that is active against both bacterial toxins and the endogenous pore, gasdermin D, a terminal effector of pyroptosis. Activation of the ubiquitin ligase NEDD4 by potassium efflux mobilizes LITAF to recruit the endosomal sorting complexes required for transport (ESCRT) machinery to repair damaged membrane. Cells lacking LITAF, or carrying naturally occurring disease-associated mutations of LITAF, are highly susceptible to pore-induced death. Notably, LITAF-mediated repair occurs at endosomal membranes, resulting in expulsion of damaged membranes as exosomes, rather than through direct excision of pores from the surface plasma membrane. These results identify LITAF as a key effector that links sensing of cellular damage to repair.
Topics: Animals; Cell Death; Cell Membrane; Pyroptosis; Endosomes; Bacterial Toxins
PubMed: 38181093
DOI: 10.1126/sciimmunol.abq6541 -
Developmental Cell Aug 2023Membranes are essential for life. They act as semi-permeable boundaries that define cells and organelles. In addition, their surfaces actively participate in biochemical... (Review)
Review
Membranes are essential for life. They act as semi-permeable boundaries that define cells and organelles. In addition, their surfaces actively participate in biochemical reaction networks, where they confine proteins, align reaction partners, and directly control enzymatic activities. Membrane-localized reactions shape cellular membranes, define the identity of organelles, compartmentalize biochemical processes, and can even be the source of signaling gradients that originate at the plasma membrane and reach into the cytoplasm and nucleus. The membrane surface is, therefore, an essential platform upon which myriad cellular processes are scaffolded. In this review, we summarize our current understanding of the biophysics and biochemistry of membrane-localized reactions with particular focus on insights derived from reconstituted and cellular systems. We discuss how the interplay of cellular factors results in their self-organization, condensation, assembly, and activity, and the emergent properties derived from them.
Topics: Cell Membrane; Membranes; Signal Transduction; Cell Nucleus
PubMed: 37419118
DOI: 10.1016/j.devcel.2023.06.001 -
Biochimica Et Biophysica Acta.... Oct 2023Eukaryotic plasma membranes (PMs) are energized by electrogenic P-type ATPases that generate either Na or H motive forces to drive Na and H dependent transport... (Review)
Review
Eukaryotic plasma membranes (PMs) are energized by electrogenic P-type ATPases that generate either Na or H motive forces to drive Na and H dependent transport processes, respectively. For this purpose, animal rely on Na/K-ATPases whereas fungi and plants employ PM H-ATPases. Prokaryotes, on the other hand, depend on H or Na-motive electron transport complexes to energize their cell membranes. This raises the question as to why and when electrogenic Na and H pumps evolved? Here it is shown that prokaryotic Na/K-ATPases have near perfect conservation of binding sites involved in coordination of three Na and two K ions. Such pumps are rare in Eubacteria but are common in methanogenic Archaea where they often are found together with P-type putative PM H-ATPases. With some exceptions, Na/K-ATPases and PM H-ATPases are found everywhere in the eukaryotic tree of life, but never together in animals, fungi and land plants. It is hypothesized that Na/K-ATPases and PM H-ATPases evolved in methanogenic Archaea to support the bioenergetics of these ancestral organisms, which can utilize both H and Na as energy currencies. Both pumps must have been simultaneously present in the first eukaryotic cell, but during diversification of the major eukaryotic kingdoms, and at the time animals diverged from fungi, animals kept Na/K-ATPases but lost PM H-ATPases. At the same evolutionary branch point, fungi did loose Na/K-ATPases, and their role was taken over by PM H-ATPases. An independent but similar scenery emerged during terrestrialization of plants: they lost Na/K-ATPases but kept PM H-ATPases.
Topics: Animals; Sodium-Potassium-Exchanging ATPase; Proton-Translocating ATPases; Proton Pumps; Cell Membrane; Eukaryota; Archaea; Fungi; Plants
PubMed: 37301269
DOI: 10.1016/j.bbamcr.2023.119511 -
Frontiers in Immunology 2023T cell activation is initiated by the recognition of specific antigenic peptides and subsequently accomplished by complex signaling cascades. These aspects have been... (Review)
Review
T cell activation is initiated by the recognition of specific antigenic peptides and subsequently accomplished by complex signaling cascades. These aspects have been extensively studied for decades as pivotal factors in the establishment of adaptive immunity. However, how receptors or signaling molecules are organized in the resting state prior to encountering antigens has received less attention. Recent advancements in super-resolution microscopy techniques have revealed topographically controlled pre-formed organization of key molecules involved in antigen recognition and signal transduction on microvillar projections of T cells before activation and substantial effort has been dedicated to characterizing the topological structure of resting T cells over the past decade. This review will summarize our current understanding of how key surface receptors are pre-organized on the T-cell plasma membrane and discuss the potential role of these receptors, which are preassembled prior to ligand binding in the early activation events of T cells.
Topics: T-Lymphocytes; Signal Transduction; Cell Membrane; Leukocyte Common Antigens; Cell Communication; Antigens
PubMed: 37795089
DOI: 10.3389/fimmu.2023.1264721