Phosphoinositides (PIs) are phospholipids that perform crucial cell functions, ranging from cell migration and signaling to membrane trafficking, by serving as signposts of compartmental membrane ...identity. Although phosphatidylinositol 4,5-bisphosphate, 3-phosphate, and 3,5-bisphosphate are commonly considered as hallmarks of the plasma membrane, endosomes, and lysosomes, these compartments contain other functionally important PIs. Here, we review the roles of PIs in different compartments of the endolysosomal system in mammalian cells and discuss the mechanisms that spatiotemporally control PI conversion in endocytosis and endolysosomal membrane dynamics during endosome maturation and sorting. As defective PI conversion underlies human genetic diseases, including inherited myopathies, neurological disorders, and cancer, PI-converting enzymes represent potential targets for drug-based therapies.
Highlights • Lipids function as key regulators of neurotransmission. • Cholesterol may serve as a membrane organizer during synaptic vesicle exo- and endocytosis. • Sphingolipids and their ...metabolites may regulate synaptic vesicle exo-endocytosis. • Phosphoinositides act as protein-recruitment hubs potentially coupling exo- and endocytosis at synapses.
The function of the nervous system depends on the exocytotic release of neurotransmitter from synaptic vesicles (SVs). To sustain neurotransmission, SV membranes need to be retrieved, and SVs have to ...be reformed locally within presynaptic nerve terminals. In spite of more than 40 years of research, the mechanisms underlying presynaptic membrane retrieval and SV recycling remain controversial. Here, we review the current state of knowledge in the field, focusing on the molecular mechanism involved in presynaptic membrane retrieval and SV reformation. We discuss the challenges associated with studying these pathways and present perspectives for future research.
Neurotransmission depends on exocytosis of synaptic vesicles, which subsequently need to be retrieved and reformed. Here, Kononenko and Haucke review the mechanisms of membrane retrieval and synaptic vesicle reformation and present perspectives for future research.
•Neurotransmitter release from synaptic vesicles occurs at active zone release sites.•Presynaptic active zones comprise an assembly of large multidomain proteins.•Exo- and endocytosis at active zones ...may be functionally and physically linked.•Modes and mechanisms of exo-endocytic coupling are presented and discussed.
Brain function depends on the ability of neurons to communicate with each other via the regulated exocytosis of neurotransmitter-containing synaptic vesicles (SVs) at specialized presynaptic release sites termed active zones (AZs). The presynaptic AZ comprises an assembly of large multidomain proteins that link the machinery for vesicle fusion to sites of voltage-dependent Ca2+ entry. Following SV fusion at AZ release sites SV membranes are retrieved by compensatory endocytosis, and SVs are reformed. Recent data suggest that Ca2+-triggered SV exocytosis at AZs and endocytic retrieval of SVs may be functionally and physically linked. Here we discuss the evidence supporting such exo-endocytic coupling as well as possible modes and mechanisms that may underlie coupling of exocytosis and endocytosis at and around AZs in presynaptic nerve terminals. As components of the exo-endocytic machinery at synapses have been linked to neurological and neuropsychiatric disorders, understanding the mechanisms that couple exocytosis and endocytosis at AZs may be of importance for developing novel therapies to treat these diseases.
BAR domain superfamily proteins have emerged as central regulators of dynamic membrane remodeling, thereby playing important roles in a wide variety of cellular processes, such as organelle ...biogenesis, cell division, cell migration, secretion, and endocytosis. Here, we review the mechanistic and structural basis for the membrane curvature-sensing and deforming properties of BAR domain superfamily proteins. Moreover, we summarize the present state of knowledge with respect to their regulation by autoinhibitory mechanisms or posttranslational modifications, and their interactions with other proteins, in particular with GTPases, and with membrane lipids. We postulate that BAR superfamily proteins act as membrane-deforming scaffolds that spatiotemporally orchestrate membrane remodeling.
Neurons are long-lived cells that communicate via release of neurotransmitter at specialized contacts termed synapses. The maintenance of neuronal health and the regulation of synaptic function ...requires the efficient removal of damaged or dispensable proteins and organelles from synapses. How macroautophagy/autophagy contributes to neuronal and synaptic protein turnover, and what its main physiological substrates are in healthy neurons is largely unknown. We have now shown that loss of neuronal autophagy facilitates presynaptic neurotransmission by controlling the axonal endoplasmic reticulum and, thereby, axonal and synaptic calcium homeostasis.
Lysosomes serve as cellular degradation and signalling centres that coordinate metabolism in response to intracellular cues and extracellular signals. Lysosomal capacity is adapted to cellular needs ...by transcription factors, such as TFEB and TFE3, which activate the expression of lysosomal and autophagy genes. Nuclear translocation and activation of TFEB are induced by a variety of conditions such as starvation, lysosome stress and lysosomal storage disorders. How these various cues are integrated remains incompletely understood. Here, we describe a pathway initiated at the plasma membrane that controls lysosome biogenesis via the endocytic regulation of intracellular ion homeostasis. This pathway is based on the exo-endocytosis of NHE7, a Na
/H
exchanger mutated in X-linked intellectual disability, and serves to control intracellular ion homeostasis and thereby Ca
/calcineurin-mediated activation of TFEB and downstream lysosome biogenesis in response to osmotic stress to promote the turnover of toxic proteins and cell survival.
Mechanisms that ensure robust long-term performance of synaptic transmission over a wide range of activity are crucial for the integrity of neuronal networks, for processing sensory information and ...for the ability to learn and store memories. Recent experiments have revealed that such robust performance requires a tight coupling between exocytic vesicle fusion at defined release sites and endocytic retrieval of synaptic vesicle membranes. Distinct presynaptic scaffolding proteins are essential for fulfilling this requirement, providing either ultrastructural coordination or acting as signalling hubs.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of tethers to contact sites between the endoplasmic reticulum ...(ER) and the plasma membrane is often triggered by calcium. Here we reveal a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate IP
accumulation upon loss of the inositol 5-phosphatase INPP5A or receptor signaling triggers depletion of cholesterol and associated Gb3 from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP
hydrolysis in the control of lipid exchange at membrane contact sites.
Neurotransmission is based on the exocytic fusion of synaptic vesicles (SVs) followed by endocytic membrane retrieval and the reformation of SVs. Recent data suggest that at physiological temperature ...SVs are internalized via clathrin-independent ultrafast endocytosis (UFE) within hundreds of milliseconds, while other studies have postulated a key role for clathrin-mediated endocytosis (CME) of SV proteins on a timescale of seconds to tens of seconds. Here we demonstrate using cultured hippocampal neurons as a model that at physiological temperature SV endocytosis occurs on several timescales from less than a second to several seconds, yet, is largely independent of clathrin. Clathrin-independent endocytosis (CIE) of SV membranes is mediated by actin-nucleating formins such as mDia1, which are required for the formation of presynaptic endosome-like vacuoles from which SVs reform. Our results resolve previous discrepancies in the field and suggest that SV membranes are predominantly retrieved via CIE mediated by formin-dependent actin assembly.
•SV proteins are retrieved on multiple timescales at physiological temperature•Clathrin/AP-2 are largely dispensable for SV endocytosis in hippocampal neurons•SV endocytosis is mediated by formin-dependent actin assembly•Formin activity is required for formation of synaptic endosome-like vacuoles
Neurotransmission requires exo-/endocytic cycling of synaptic vesicles (SVs). The timescale and mechanism of SV endocytosis remain debated. Soykan et al. show that SV proteins are retrieved on multiple timescales at physiological temperature, largely via clathrin-independent endocytosis mediated by formins.
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