Myosin VI small insert isoform maintains exocytosis by tethering secretory granules to the cortical actin

Tomatis, Vanesa M.; Papadopulos, Andreas; Malintan, Nancy T.; Martin, Sally; Wallis, Tristan P.; Gormal, Rachel S.; Kendrick‐Jones, John; Buß, Folma; Meunier, Frédéric A.

doi:10.1083/jcb.201204092

Cited by 62 publications

(63 citation statements)

References 76 publications

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“…6a-d). Co-localization between TNF and Iba1 or GFAP was analysed using Imaris software to derive Pearson's correlation coefficients (r) 37,38 . In brain slices from wild-type mice after I/R, co-labelled Iba1/TNF-positive cells were particularly abundant in the ischaemic penumbra ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Z-series through the coronal sections, 5-9.8 mm in the infarct or penumbra regions to 9.8 mm in the contralateral regions were captured on an inverted confocal microscope (LSM510; Carl Zeiss) with a Â 20 (numerical aperture 0.75) objective using the associated ZEN software. LSM images were analysed in Imaris Coloc (version 7.2.3; Bitplane) and Pearson's correlation coefficient (r) values were calculated to measure the correlation dependency of colocalized voxels in three dimension between separate colour channels 37,38 . For experiments in BM chimeric mice, brains were cut into 40 mm coronal sections with a microtome (1:4 series) and subjected to free-floating immunofluorescence staining.…”

Section: Article Nature Communications | Doi: 101038/ncomms4450mentioning

confidence: 99%

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PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

et al. 2014

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Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kd) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kd inhibition confers protection in ischaemia/ reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kd inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kd (p110d D910A/D910A ) or wild-type mice pre-or post-treated with the PI3Kd inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kd as a potential therapeutic target in ischaemic stroke.

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Section: Resultsmentioning

confidence: 99%

Section: Article Nature Communications | Doi: 101038/ncomms4450mentioning

confidence: 99%

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

et al. 2014

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“…In brief, mCherry was amplified from pmCherry-C1 (Takara Bio Inc.) by PCR using the following primers: forward, 5 0 -ATCGATAAGCTCATGGTG GCAAGGGCGAG-3 0 ; and reverse, 5 0 -CAAGTAAAACCTCTACAAATGTGGT ATGGC-3 0 . It was then subcloned into pCMV-NPY-emerald GFP using ClaI and BamHI, replacing emerald GFP 10 .…”

Section: Methodsmentioning

confidence: 99%

“…We then performed SV tracking before and during stimulation in both PC12-DKD cells and Munc18-1-rescued PC12-DKD cells (Fig. 6d) and measured the mean squared displacements (MSDs) of all trajectories to calculate cage radii and to assess vesicle mobility 10 . In the Munc18-1-rescued cells, we found a cage radius of 0.14±0.02 mm (n ¼ 6; Fig.…”

Section: Svs and Cortical Actin Approach The Plasmalemma On Stimulationmentioning

confidence: 99%

“…The cortical actin network plays a major role in regulated exocytosis 2,7 and has been shown to interact with SVs in various ways, in particular through the action of myosin molecular motors 8,9 . SVs can be tethered to the cortical actin network by myosin VI in an activity-dependent manner 10 , and can also be transported along actin fibres by myosin Va 11 . Recent work has also highlighted a role for myosin II in exocytosis [12][13][14][15][16][17] , as well as demonstrating its ability to maintain the cortical actin network under tension [18][19][20] .…”

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confidence: 99%

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Activity-driven relaxation of the cortical actomyosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking

et al. 2015

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In neurosecretory cells, secretory vesicles (SVs) undergo Ca 2 þ -dependent fusion with the plasma membrane to release neurotransmitters. How SVs cross the dense mesh of the cortical actin network to reach the plasma membrane remains unclear. Here we reveal that, in bovine chromaffin cells, SVs embedded in the cortical actin network undergo a highly synchronized transition towards the plasma membrane and Munc18-1-dependent docking in response to secretagogues. This movement coincides with a translocation of the cortical actin network in the same direction. Both effects are abolished by the knockdown or the pharmacological inhibition of myosin II, suggesting changes in actomyosin-generated forces across the cell cortex. Indeed, we report a reduction in cortical actin network tension elicited on secretagogue stimulation that is sensitive to myosin II inhibition. We reveal that the cortical actin network acts as a 'casting net' that undergoes activity-dependent relaxation, thereby driving tethered SVs towards the plasma membrane where they undergo Munc18-1-dependent docking.

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TheMYO6 interactome: selective motor‐cargo complexes for diverse cellular processes

et al. 2019

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Myosins of class VI (MYO6) are unique actin‐based motor proteins that move cargo towards the minus ends of actin filaments. As the sole myosin with this directionality, it is critically important in a number of biological processes. Indeed, loss or overexpression of MYO6 in humans is linked to a variety of pathologies including deafness, cardiomyopathy, neurodegenerative diseases as well as cancer. This myosin interacts with a wide variety of direct binding partners such as for example the selective autophagy receptors optineurin, TAX1BP1 and NDP52 and also Dab2, GIPC, TOM1 and LMTK2, which mediate distinct functions of different MYO6 isoforms along the endocytic pathway. Functional proteomics has recently been used to identify the wider MYO6 interactome including several large functionally distinct multi‐protein complexes, which highlight the importance of this myosin in regulating the actin and septin cytoskeleton. Interestingly, adaptor‐binding not only triggers cargo attachment, but also controls the inactive folded conformation and dimerisation of MYO6. Thus, the C‐terminal tail domain mediates cargo recognition and binding, but is also crucial for modulating motor activity and regulating cytoskeletal track dynamics.

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Myosin VI small insert isoform maintains exocytosis by tethering secretory granules to the cortical actin

Abstract: Phosphorylation of the DYD motif of myosin VI small insert isoform controls the sustainability of exocytosis by tethering secretory granules to the cortical actin network.

Cited by 62 publications

References 76 publications

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model

Activity-driven relaxation of the cortical actomyosin II network synchronizes Munc18-1-dependent neurosecretory vesicle docking

TheMYO6 interactome: selective motor‐cargo complexes for diverse cellular processes

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