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A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding
Insulin secretion adapts to metabolic needs, but how this happens over the short term is not clear. Here the authors show this involves upregulation of beta-cell exocytosis and requires the SUMO-protease SENP1, which responds to redox state in a zinc-dependent manner.
- Haopeng Lin
- , Kunimasa Suzuki
- & Patrick E. MacDonald
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Article
| Open Access
Synaptotagmin-7 outperforms synaptotagmin-1 to promote the formation of large, stable fusion pores via robust membrane penetration
Synaptotagmin-1 and -7 are calcium sensors that distinctly drive vesicular exocytosis. Here, using wild-type proteins but manipulating the composition of the target membranes, the authors show that synaptotagmin-7 is unusually robust at penetrating membranes.
- Kevin C. Courtney
- , Taraknath Mandal
- & Edwin R. Chapman
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| Open Access
Intermediate filaments associate with aggresome-like structures in proteostressed C. elegans neurons and influence large vesicle extrusions as exophers
High neuronal proteostress can trigger the production of aggregate-filled exophers in C. elegans. Here authors show that such extrusion relies on aggregate-associated intermediate filaments and adaptors.
- Meghan Lee Arnold
- , Jason Cooper
- & Monica Driscoll
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Article
| Open Access
Tetraspanin-8 sequesters syntaxin-2 to control biphasic release propensity of mucin granules
The mechanisms regulating granule secretion are not fully understood. Here the authors show that tetraspanin-8 sequesters syntaxin-2 at the cell surface, limiting the syntaxin available for fusion and the quantities of mucin secreted. This mechanism may also apply to insulin release
- José Wojnacki
- , Agustin Leonardo Lujan
- & Vivek Malhotra
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Article
| Open Access
Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis
The authors describe the mechanism of exo-endocytosis coupling at synapses. They find that actin forms a ring around the region of exocytosis. This ring conserves membrane area, allowing induction of inward membrane buckling following exocytosis.
- Tyler H. Ogunmowo
- , Haoyuan Jing
- & Jian Liu
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Article
| Open Access
Exocytosis of the silicified cell wall of diatoms involves extensive membrane disintegration
Exocytosis is a fundamental cellular process. Here, the authors report an unusual exocytosis mechanism in the silicified cell wall of diatoms, in which membrane patches are discarded.
- Diede de Haan
- , Lior Aram
- & Assaf Gal
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Article
| Open Access
Plasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis
Kang and colleagues find that plasma membrane flipping of Syntaxin-2 from inside (inhibitory) to outside (relief of inhibition) of pancreatic β-cells helps fine-tune insulin secretion. Increasing this flipping efficiency can alleviate the impaired insulin secretion in diabetes.
- Fei Kang
- , Li Xie
- & Herbert Y. Gaisano
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| Open Access
A degradative to secretory autophagy switch mediates mitochondria clearance in the absence of the mATG8-conjugation machinery
The mechanisms underlying mitochondrial quality control are not fully understood. Here the authors identify a switch from degradative to secretory autophagy in the absence of the mATG8-conjugation system, termed Autophagic Secretion of Mitochondria.
- Hayden Weng Siong Tan
- , Guang Lu
- & Han-Ming Shen
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Article
| Open Access
Molecular mechanics underlying flat-to-round membrane budding in live secretory cells
Shin et al. report the molecular mechanics of membrane budding: actin and dynamin pull membrane inward to form a Λ-shape profile; dynamin helices convert Λ- to Ω-shape by constricting Λ’s base, and then constrict Ω-profile’s pore to form a vesicle.
- Wonchul Shin
- , Ben Zucker
- & Ling-Gang Wu
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Article
| Open Access
P-selectin mobility undergoes a sol-gel transition as it diffuses from exocytosis sites into the cell membrane
P-selectin recruits leucocytes to regions of blood vessel damage. Using single molecule imaging, we find newly secreted P-selectin spreads rapidly across the plasma membrane and then becomes immobilized and better-suited to leucocyte capture.
- Nicola Hellen
- , Gregory I. Mashanov
- & Tom Carter
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Article
| Open Access
An active tethering mechanism controls the fate of vesicles
Molecular tethers physically bridge transport vesicles to their target membranes as a prerequisite step for fusion. Here the authors control vesicle tethering using optogenetic approaches to study the interplay between vesicle tethering and fusion.
- Seong J. An
- , Felix Rivera-Molina
- & Derek Toomre
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Article
| Open Access
TMEM16F and dynamins control expansive plasma membrane reservoirs
Cells locally expand and retract their surface in response to environmental factors such as changes in membrane tension. Here the authors show the membrane adapter, dynamin2, locally constricts surface membrane to form an isolated but contiguous membrane reservoir that can open upon phospholipid scrambling via TMEM16F.
- Christine Deisl
- , Donald W. Hilgemann
- & Michael Fine
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Article
| Open Access
Extracellular vesicles and exosomes generated from cystic renal epithelial cells promote cyst growth in autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease is characterized by the formation of cysts in the kidney. Here the authors show that cystic extracellular vesicles/exosomes play a critical role in regulating the biology and function of adjacent cells, including renal epithelial cells, fibroblasts and macrophages, and contribute to renal cyst growth.
- Hao Ding
- , Linda Xiaoyan Li
- & Xiaogang Li
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| Open Access
The nanoscale molecular morphology of docked exocytic dense-core vesicles in neuroendocrine cells
The molecular organization of exocytic vesicles regulates their transport and fusion. Prasai, Taraska, and colleagues use correlative light and electron microscopy, along with 3D tomography and gold labeling, to directly map proteins on single exocytic organelles at the plasma membrane.
- Bijeta Prasai
- , Gideon J. Haber
- & Justin W. Taraska
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| Open Access
pHmScarlet is a pH-sensitive red fluorescent protein to monitor exocytosis docking and fusion steps
A number of pH-sensitive fluorescent proteins exist which enable monitoring of some but not all steps of exocytosis. Here the authors engineer a bright, photostable red pH-sensitive fluorescent protein, pHmScarlet, to allow visualisation of the docking and fusion events of exocytosis.
- Anyuan Liu
- , Xiaoshuai Huang
- & Pingyong Xu
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Article
| Open Access
Conserved arginine residues in synaptotagmin 1 regulate fusion pore expansion through membrane contact
Synaptotagmin 1 (Syt1) is the calcium sensor for fast synchronous neurotransmitter release but the mechanism by which it functions is still under debate. Here, the authors combine EPR measurements and functional studies and observe that different faces of the Syt1 C2B domain play different roles in regulating neurotransmitter release and they show that the expansion of the fusion pore is mediated by membrane contact of the C2B arginine apex.
- Sarah B. Nyenhuis
- , Nakul Karandikar
- & David S. Cafiso
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| Open Access
Asynchronous release sites align with NMDA receptors in mouse hippocampal synapses
Action potentials induce synchronous and asynchronous release of neurotransmitters. Here, the authors show that the synchronous and asynchronous release sites are aligned with AMPARs and NMDARs, respectively, in mouse hippocampal synapses. This organization allows efficient activation of NMDARs.
- Shuo Li
- , Sumana Raychaudhuri
- & Shigeki Watanabe
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Article
| Open Access
Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes
Glucagon is elevated Type-2 diabetes, which contributes to poor glucose control in patients with the disease. Here the authors report that secretion of the hormone is controlled by paracrine inhibition, and that resistance of α-cells to somatostatin can explain hyperglucagonemia in type-2 diabetes.
- Muhmmad Omar-Hmeadi
- , Per-Eric Lund
- & Sebastian Barg
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| Open Access
Endophilin-A coordinates priming and fusion of neurosecretory vesicles via intersectin
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.
- Sindhuja Gowrisankaran
- , Sébastien Houy
- & Ira Milosevic
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| Open Access
Resolving kinetic intermediates during the regulated assembly and disassembly of fusion pores
SNAREs mediate the formation of a fusion pore during exocytosis which connects the lumen of a vesicle with the extracellular space. Here, authors use single molecule approaches to define the role of synaptotagmin 1 and NSF in synaptic pore formation and dissolution.
- Debasis Das
- , Huan Bao
- & Edwin R. Chapman
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| Open Access
Munc18-1 is crucial to overcome the inhibition of synaptic vesicle fusion by αSNAP
Munc18-1 and Munc13-1 are key for the exquisite regulation of neurotransmitter release. Here biophysical experiments show how αSNAP inhibits liposome fusion mediated by the neuronal SNAREs and how Munc18-1 overcomes this inhibition, ensuring that release depends on Munc18-1 and Munc13-1.
- Karolina P. Stepien
- , Eric A. Prinslow
- & Josep Rizo
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Article
| Open Access
A lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites
Plasmodium and Toxoplasma parasites rely on rhoptry exocytosis for invasion, but the underlying mechanism is not known. Here, Suarez et al. characterize rhoptry apical surface proteins (RASP) that localize to the rhoptry cap and bind charged lipids, and are essential for rhoptry secretion and invasion.
- Catherine Suarez
- , Gaëlle Lentini
- & Maryse Lebrun
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| Open Access
In vitro fusion of single synaptic and dense core vesicles reproduces key physiological properties
Regulated exocytosis of neuronal synaptic vesicles is substantially faster than that of endocrine dense core vesicles despite similar molecular machineries. Here authors compare SNARE-mediated fusion of purified synaptic vesicles with insulin vesicles and see disparities in calcium-triggered fusion rates.
- Alex J. B. Kreutzberger
- , Volker Kiessling
- & Lukas K. Tamm
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| Open Access
A protein complex required for polar growth of rhizobial infection threads
Many legumes accommodate rhizobial symbionts via transcellular infection threads. Here the authors show that in Medicago root hairs, polar growth of the infection thread requires a tip-localized protein complex consisting of VPY and VPY-like proteins that are stabilized by the E3 ligase LIN, as well as an exocyst complex subunit.
- Cheng-Wu Liu
- , Andrew Breakspear
- & Jeremy D. Murray
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Article
| Open Access
WDFY2 restrains matrix metalloproteinase secretion and cell invasion by controlling VAMP3-dependent recycling
WDFY2 is known as a tumour suppressor but its function is unclear. Here, the authors show that WDFY2 interacts with the v-SNARE VAMP3, leading to a suppression of the metalloprotease MT1-MMP secretion, suggesting that WDFY2 acts a tumour suppressor by suppressing MT1-MMP secretion.
- Marte Sneeggen
- , Nina Marie Pedersen
- & Kay Oliver Schink
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Article
| Open Access
Anchoring cortical granules in the cortex ensures trafficking to the plasma membrane for post-fertilization exocytosis
Mammalian eggs require a single sperm for viable fertilization, and cortical granule exocytosis prevents additional sperm binding. Vogt et al. image at single granule resolution to document that cortical granule anchoring in the cortex ensures proper trafficking, exocytosis and polyspermy block.
- Edgar-John Vogt
- , Keizo Tokuhiro
- & Jurrien Dean
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| Open Access
Underpinning heterogeneity in synaptic transmission by presynaptic ensembles of distinct morphological modules
The mechanisms underlying synaptic heterogeneity of neurotransmission at mature calyx synapses remain unclear. Here, authors identify two morphological modules that have distinct topology of calcium channel clusters and spatial coupling distance to synaptic vesicles, which may account for different release probability and short-term plasticity in calyces with differing morphology.
- Adam Fekete
- , Yukihiro Nakamura
- & Lu-Yang Wang
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Article
| Open Access
Exocyst dynamics during vesicle tethering and fusion
Exocyst complex tethers vesicles to plasma membranes, but assembly mechanisms remain unclear. Here, the authors use Cas9 gene editing to tag exocyst components in epithelial cells, and find that exocyst subcomplexes are recruited to membranes independently, but are both needed for vesicle fusion.
- Syed Mukhtar Ahmed
- , Hisayo Nishida-Fukuda
- & Ian G. Macara
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Article
| Open Access
Postsynaptic RIM1 modulates synaptic function by facilitating membrane delivery of recycling NMDARs in hippocampal neurons
Rab3-interacting molecules (RIMs) are a key component of the presynaptic active zone that regulate neurotransmitter release. Here, the authors show that RIM1 also has postsynaptic function to organize NMDA receptors and synaptic response.
- Jiejie Wang
- , Xinyou Lv
- & Shuang Qiu
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Article
| Open Access
Semisynthetic fluorescent pH sensors for imaging exocytosis and endocytosis
Existing pH-sensitive red fluorescent protein probes don’t perform well in monitoring exocytosis and endocytosis. Here, the authors combine organic dyes with self-labeling tags or antibodies to develop semisynthetic protein conjugates that can image synaptic vesicle fusion events in living cells.
- Magalie Martineau
- , Agila Somasundaram
- & David Perrais
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Article
| Open Access
The Par3 polarity protein is an exocyst receptor essential for mammary cell survival
The exocyst delivers basolateral proteins from the secretory pathway to the plasma membrane of epithelial cells close to tight junctions. Here the authors show that Par3 acts as a docking site for the exocyst to regulate polarized delivery of basolateral proteins and this is essential to prevent apoptosis and promote mammary cell survival.
- Syed Mukhtar Ahmed
- & Ian G. Macara
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Article
| Open Access
Zyxin regulates endothelial von Willebrand factor secretion by reorganizing actin filaments around exocytic granules
The adaptor protein zyxin is known for its mechanosensing function in the maintenance of actin network. Here the authors show that zyxin is key to blood homeostasis and thrombosis by controlling the endothelial release of von Willebrand factor and the formation of actin scaffolds on exocytic granules.
- Xiaofan Han
- , Pin Li
- & Jincai Luo
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Article
| Open Access
Sec3 promotes the initial binary t-SNARE complex assembly and membrane fusion
Membrane fusion during exocytosis is mediated by interaction between SNARE proteins on vesicles and the cell membrane, but how SNARE complex assembly is initiated remains unknown. Here, the authors show that interaction of Sec3 with Sso2 on the plasma membrane promotes formation of an Sso2–Sec9 complex, an early step in SNARE assembly, likely by inhibiting Sso2 auto-inhibition.
- Peng Yue
- , Yubo Zhang
- & Wei Guo
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Article
| Open Access
ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins
Multivesicular bodies (MVB) are endosomal compartments that can either fuse with the plasma membrane for the secretion of exosomes, or fuse with the lysosome and be degraded along with their contents. Here, the authors show that ISGylation of the MVB protein TSG101 impairs exosome secretion and acts as a regulator of MVB fate.
- Carolina Villarroya-Beltri
- , Francesc Baixauli
- & Francisco Sánchez-Madrid
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Article
| Open Access
Actin dynamics provides membrane tension to merge fusing vesicles into the plasma membrane
As vesicles fuse to the plasma membrane, they form intermediate Ω-shaped structures followed by either closure of the pore or full merging with the plasma membrane. Here Wen et al. show that dynamic actin assembly provides membrane tension to promote Ω merging in neuroendocrine cells and synapses.
- Peter J. Wen
- , Staffan Grenklo
- & Ling-Gang Wu
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Article
| Open Access
CLIC4 regulates apical exocytosis and renal tube luminogenesis through retromer- and actin-mediated endocytic trafficking
Chloride intracellular channel (CLIC) 4 is an ion channel, localized in the cytoplasm, and first identified as an actin binding protein. Here, Chou et al.knockout CLIC4 in mice and observe tubulogenesis and renal proximal tubule dilation defects, which is caused by irregular actin and endosomal trafficking.
- Szu-Yi Chou
- , Kuo-Shun Hsu
- & Ching-Hwa Sung
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Article
| Open Access
Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo
The cytoskeleton plays a crucial role in secretion. Here Tran et al.demonstrate that cortical actin is rearranged at the site of vesicle fusion and recruited to fused secretory granules in Drosophila salivary glands, and show that branched actin nucleators are required for cargo expulsion.
- Duy T. Tran
- , Andrius Masedunskas
- & Kelly G. Ten Hagen
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Article
| Open Access
Presynaptic spinophilin tunes neurexin signalling to control active zone architecture and function
Synaptic assembly depends on trans-synaptic Neurexin/Neuroligin signalling. Here, Muhammad et al. show that Spinophilin, a pre-synaptic scaffolding protein, interacts with Neurexin, in competition with Syd-1, to regulate the formation and function of synaptic active zones at Drosophilaneuromuscular junctions.
- Karzan Muhammad
- , Suneel Reddy-Alla
- & Stephan J. Sigrist
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Article
| Open Access
Wall mechanics and exocytosis define the shape of growth domains in fission yeast
Cell shape is determined by a combination of biochemical regulation and mechanical forces. By imaging the dynamic behaviour of growth regulatory proteins in fission yeast and integrating these data within a mechanical model, Abenza et al. find that exocytosis plays a dominant role in shaping growth domains.
- Juan F. Abenza
- , Etienne Couturier
- & Rafael E. Carazo Salas
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Article
| Open Access
Two-photon fluorescence lifetime imaging of primed SNARE complexes in presynaptic terminals and β cells
Synaptic vesicles are held in a fusion-competent state prior to their rapid release, which is thought to depend upon formation of trans-SNARE complexes. Takahashi et al. directly image this primed state using FLIM/FRET, and demonstrate differences in basal SNARE organization between neurons and β cells.
- Noriko Takahashi
- , Wakako Sawada
- & Haruo Kasai
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Article
| Open Access
Diffusional spread and confinement of newly exocytosed synaptic vesicle proteins
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.
- Niclas Gimber
- , Georgi Tadeus
- & Volker Haucke
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Article
| Open Access
SUMOylation of synapsin Ia maintains synaptic vesicle availability and is reduced in an autism mutation
Synapsins anchor synaptic vesicles (SVs) to the actin cytoskeleton to establish the reserve vesicle pool. Here Tanget al. show that SUMOylation of synapsin 1a enhances its interaction with SVs to promote efficient reclustering following stimulation, and a mutation linked to autism and epilepsy leads to defective SUMOylation.
- Leo T. -H. Tang
- , Tim J. Craig
- & Jeremy M. Henley
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Article
| Open Access
Tropomodulin3 is a novel Akt2 effector regulating insulin-stimulated GLUT4 exocytosis through cortical actin remodeling
Insulin-stimulated GLUT4-storage vesicle fusion with the plasma membrane depends on activity of Akt2 and its downstream effectors. Here Lim et al.identify the actin-capping protein tropomodulin 3 as a novel Akt2 effector that remodels cortical actin to help facilitate GLUT4 membrane insertion.
- Chun-Yan Lim
- , Xuezhi Bi
- & Weiping Han
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Article
| Open Access
A molecular toggle after exocytosis sequesters the presynaptic syntaxin1a molecules involved in prior vesicle fusion
Synaptic vesicle fusion involves a multi-protein assembly called the SNARE complex that is tightly regulated both spatially and temporally. Here Kavanagh et al. show that after vesicle fusion and SNARE complex disassembly in the synapse, the SNARE protein syntaxin1a is sequestered in a monomeric form by munc18-1, preventing ectopic SNARE complex assembly.
- Deirdre M. Kavanagh
- , Annya M. Smyth
- & Rory R. Duncan
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Membrane deformation and scission by the HSV-1 nuclear egress complex
Two viral proteins form the nuclear egress complex of herpesviruses, which is essential for the exit of nascent viral capsids from the cell nucleus. Here, the authors use synthetic lipid vesicles to show that the complex can mediate membrane budding in the absence of other cellular factors.
- Janna M. Bigalke
- , Thomas Heuser
- & Ekaterina E. Heldwein
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Contact-induced clustering of syntaxin and munc18 docks secretory granules at the exocytosis site
Insulin secretory granules dock at the plasma membrane in a syntaxin-dependent manner prior to exocytosis. Gandasi et al. demonstrate that clusters of syntaxin form de novoat the site of contact, suggesting that such clusters do not act as preformed docking receptor.
- Nikhil R. Gandasi
- & Sebastian Barg
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Article
| Open Access
Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density
Mutations in the fragile X mental retardation protein are implicated in synaptic dysfunction in fragile X syndrome. Here, Ferron et al. show that fragile X mental retardation protein maintains proper neurotransmission by regulating the density of N-type calcium channels in the presynaptic terminal.
- Laurent Ferron
- , Manuela Nieto-Rostro
- & Annette C. Dolphin
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Post-fusion structural changes and their roles in exocytosis and endocytosis of dense-core vesicles
Fusion of vesicles with the plasma membrane generates omega-shaped intermediates that are thought to either dilate until flat or less frequently, undergo pore closure. Chiang et al.reveal that in chromaffin cells, these structures do not dilate, but change in size before pore closure or shrink until undetectable.
- Hsueh-Cheng Chiang
- , Wonchul Shin
- & Ling-Gang Wu
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Non-uniform membrane diffusion enables steady-state cell polarization via vesicular trafficking
The mechanism by which proteins become polarized to a specific cortical site in budding yeast cells has been a topic of recent debate. Slaughter et al.show that differing diffusion rates of Cdc42 within plasma membrane environments sustain the polarized state.
- Brian D. Slaughter
- , Jay R. Unruh
- & Rong Li
Tomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes