Search

A mechanism for phosphoinositide conversion at endosomes to enable exit from the endosomal system, suggesting that defective phosphoinositide conversion at endosomes underlies X-linked centronuclear myopathy.

Phosphoinositides are important regulators of intracellular membrane traffic, and although the role of PI(4,5)P₂ has been well characterised, the function of PI(3,4)P₂ remains unclear; here the formation of PI(3,4)P₂ by the class II phosphatidylinositol-3-kinase C2α enzyme is shown to control clathrin-mediated endocytosis.

Meshworks of claudin polymers control the paracellular transport and barrier properties of epithelial tight junctions. Here, the authors show different claudin nanoscale organization principles, finding that claudin segregation enables barrier formation and paracellular ion flux across tight junctions.

The endocytic adaptor protein complex AP-2 is mostly known for its role in endocytosis and in synaptic vesicle reformation. Here the authors show that AP-2 also mediates retrograde transport of TrkB-containing autophagosomes in neurons; this process promotes neuronal complexity and prevents the degeneration of cortical and thalamic neurons.

Faithful transmission of information within and between neural circuits is underpinned by tight coupling between exocytosis and endocytosis at individual synapses. In this Review, Haucke and colleagues unravel the mechanisms underlying this coupling and explain how it is crucial to robust neurotransmission.

Endocytosis is a process by which molecules gain access to a cell. An unusual mode of endocytosis has now been shown to regulate cell signalling, and to be highjacked by bacterial toxins. See Article p.460 & Letter p.493

The interplay between non-vesicular lipid transport, calcium signaling, and membrane dynamics is unclear. Here, the authors report a function for inositol triphosphate hydrolysis by the inositol 5-phosphatase INPP5A in controlling lipid exchange at interorganelle membrane contact sites between the endoplasmic reticulum and Golgi.

High-resolution structures of phosphatidylinositol 3-kinase (PI3K) type IIa unravel a coincident mechanism of lipid-induced enzyme activation and enable the development of inhibitors of class II PI3K function with applications in biomedicine.

Contact sites between the endoplasmic reticulum and the plasma membrane mediate receptor signalling. How this function is controlled physically and functionally is poorly understood. Extended synaptotagmins are now shown to shuttle the lipid metabolite diacylglycerol from the plasma membrane to the endoplasmic reticulum in receptor-stimulated cells.

Communication between cells relies on hormone release from secretory granules, but how these vesicles fuse with cell membranes is unclear. An imaging study provides in vivo evidence for a stable intermediate fusion step. See Letter p.548

Neurotransmission is mediated by synaptic vesicles (SVs) fusion with the plasma membrane near active zones. Here, Gimber et al.observe that rapid diffusional spread and confinement is followed by slow reclustering of SV proteins at the periactive endocytic zone through SV protein association with the clathrin-based machinery.

Compound library screening combined with medicinal chemistry and structural biology approaches enables the development of potent and highly selective cell-permeable small-molecule inhibitors of phosphatidylinositol 3-kinase C2α activity and function.

Charcot-Marie-Tooth (CMT) is an inherited peripheral neuropathy. Here, the authors show that Rab35 forms a complex with genes implicated in CMT, MTMR13 and MTMR2, which regulates myelin growth by controlling mTORC1 signaling through lipid turnover.

López-Hernández et al. show that exo-endocytosis of a Na⁺/H⁺ exchanger controls lysosome biogenesis through Ca²⁺/calcineurin-mediated activation of TFEB in response to osmotic stress.

The spatiotemporal regulation of membrane scaffolds recruitment and coupling between membrane deformation and fission in endocytosis are unclear. Here the authors show that lipid conversion at endocytic pits recruits SNX9, which couples local membrane constriction to fission in endocytosis.

Cells employ integrin-based adhesions with different molecular compositions to adhere to substrates. Here, the authors show that so-called “non-canonical” adhesions lacking focal adhesion components can convert to focal adhesions (and vice versa), through the selective exchange of components.

Stockhammer, Adarska et al. describe ARF1 compartments as the site of adaptor- and clathrin-dependent post-Golgi sorting. Shedding of ARF1 and maturation into recycling endosomes drives sorting of secretory and endocytic recycling cargo.

Endocytosis is critical for regulating plasma membrane composition and function. The mechanisms that control the assembly and dynamic rearrangement of the endocytic protein network to enable endocytic vesicle formation have remained elusive. Two endocytic initiator proteins are now shown to form liquid-like condensates to initiate endocytosis.

Maintaining plasma membrane tension is important for eukaryotic cells. How altered membrane tension is sensed and relayed to downstream factors, such as the target of rapamyin complex 2 (TORC2), is poorly understood. Reorganization of a signalling lipid into discrete membrane domains is now shown to inactivate TORC2 in yeast.

Caveolae can bend and flatten, but how this is regulated is not well understood. Authors use correlative super-resolution light and electron microscopy to map the key proteins that mediate curvature of the caveolar coat.

Myotubular myopathy is a severe muscle disease for which no effective treatment exists. Here, the authors show that tamoxifen ameliorates pathology and extends survival in a mouse model of the disease, and that the effect is mediated via estrogen receptor signaling and involves modulation of DNM2 expression.

Endophilins-A are conserved membrane-associated proteins required for endocytosis. Here, the authors report that endophilins-A also promote exocytosis of neurosecretory vesicles by coordinating priming and fusion through intersectin-1, independently of their roles in different types of endocytosis.

Affinity-based target isolation and X-ray crystallography enabled identification of the non-protonophore ES9-17 as an inhibitor of the clathrin heavy chain in plants, enabling disruption of endocytosis.

Viral infection from the basolateral side of intestinal epithelial cells (IECs) is shown to elicit a stronger intrinsic immune response than apical infection, an effect driven by the polarized sorting of Toll-like receptor 3. Experiments in mice and human cells suggest that the cellular polarity program is integral to the ability of IECs to tolerate gut commensals while remaining responsive to invasive pathogens.

The precise mechanisms that cause human obesity remain unknown. Here the authors illustrate how increased expression of Cadm1, a mediator of synapse assembly, is relevant to weight gain. Reduction of Cadm1 in multiple brain regions promoted weight loss, and these observations provide insight into the neuronal pathways contributing to obesity.

The authors developed small-molecule inhibitors of STOML3 oligomerization, a membrane protein that interacts with mechanosensitive ion channels, such as Piezo2. One of these molecules was effective in silencing touch receptors and reversed touch-evoked pain associated with nerve injury or diabetic neuropathy.

Wallroth et al. uncover a mechanism by which protein kinase N activates mTORC1 nutrient signalling at the lysosome by inhibiting PI3KC2-β-mediated PtdIns(3,4)P₂ synthesis downstream of mTORC2.

AMPA, NMDA or insulin can cause endocytosis of AMPA receptors. Two papers now show that these stimuli act via distinct signaling pathways, some of which also induce LTD.

Phosphoinositides are signalling, membrane lipids derived from phosphatidylinositol, whose intracellular distribution and interconversion via phosphoinositide kinases and phosphatases is tightly coupled to membrane dynamics. Accordingly, phosphoinositides are now recognized as key regulators of endocytic and exocytic traffic, the autolysosomal system, and membrane contact site organization and function.

The crystal structure of the large GTPase dynamin tetramer is presented, suggesting a mechanism by which oligomerization of dynamin is regulated, and revealing how mutations that interfere with tetramer formation and autoinhibition are of relevance to understanding the congenital muscle disorders Charcot–Marie–Tooth neuropathy and centronuclear myopathy.

Clathrin is a protein complex that has roles in endocytosis and mitosis. This Protocol describes the synthesis of the Pitstop family of clathrin inhibitors and their inactive controls.