superresolution imaging
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2021 ◽  
Vol 221 (2) ◽  
Author(s):  
Rachel M. Brunetti ◽  
Gabriele Kockelkoren ◽  
Preethi Raghavan ◽  
George R.R. Bell ◽  
Derek Britain ◽  
...  

To control their movement, cells need to coordinate actin assembly with the geometric features of their substrate. Here, we uncover a role for the actin regulator WASP in the 3D migration of neutrophils. We show that WASP responds to substrate topology by enriching to sites of inward, substrate-induced membrane deformation. Superresolution imaging reveals that WASP preferentially enriches to the necks of these substrate-induced invaginations, a distribution that could support substrate pinching. WASP facilitates recruitment of the Arp2/3 complex to these sites, stimulating local actin assembly that couples substrate features with the cytoskeleton. Surprisingly, WASP only enriches to membrane deformations in the front half of the cell, within a permissive zone set by WASP’s front-biased regulator Cdc42. While WASP KO cells exhibit relatively normal migration on flat substrates, they are defective at topology-directed migration. Our data suggest that WASP integrates substrate topology with cell polarity by selectively polymerizing actin around substrate-induced membrane deformations in the front half of the cell.


2021 ◽  
pp. 130882
Author(s):  
Álvaro Ruiz-Arias ◽  
Rocío Jurado ◽  
Francisco Fueyo-González ◽  
Rosario Herranz ◽  
Natividad Gálvez ◽  
...  

2021 ◽  
Vol 127 (12) ◽  
Author(s):  
Giacomo Sorelli ◽  
Manuel Gessner ◽  
Mattia Walschaers ◽  
Nicolas Treps

2021 ◽  
Vol 118 (33) ◽  
pp. e2102191118
Author(s):  
Hao Wang ◽  
Joshua A. Kulas ◽  
Chao Wang ◽  
David M. Holtzman ◽  
Heather A. Ferris ◽  
...  

Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβ-peptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling.


2021 ◽  
Author(s):  
Tanushree Kundu ◽  
Priyanka Dutta ◽  
Dhriti Nagar ◽  
Sankar Maiti ◽  
Aurnab Ghose

Dynamic co-regulation of the actin and microtubule subsystems enables the highly precise and adaptive remodelling of the cytoskeleton necessary for critical cellular processes, like axonal pathfinding. The modes and mediators of this interpolymer crosstalk, however, are inadequately understood. We identify Fmn2, a non-diaphanous related formin associated with cognitive disabilities, as a novel regulator of cooperative actin-microtubule remodelling in growth cones. We show that Fmn2 stabilizes microtubules in the growth cones of cultured spinal neurons and also in vivo. Superresolution imaging revealed that Fmn2 facilitates guidance of exploratory microtubules along actin bundles into the chemosensory filopodia. Using live imaging, biochemistry and single-molecule assays we show that a C-terminal domain in Fmn2 is necessary for the dynamic association between microtubules and actin filaments. In the absence of the cross- bridging function of Fmn2, filopodial capture of microtubules is compromised resulting in de-stabilized filopodial protrusions and deficits in growth cone chemotaxis. Our results uncover a critical function for Fmn2 in actin-microtubule crosstalk in neurons and demonstrate that modulating microtubule dynamics via associations with F-actin is central to directional motility.


2021 ◽  
Vol 140 ◽  
pp. 106522
Author(s):  
Famin Wang ◽  
Yun Xiao ◽  
Jiawang Zhao ◽  
Yunhai Zhang ◽  
Hangfeng Li

2021 ◽  
Vol 7 (19) ◽  
pp. eabe8349
Author(s):  
Despoina Kerselidou ◽  
Bushra Saeed Dohai ◽  
David R. Nelson ◽  
Sarah Daakour ◽  
Nicolas De Cock ◽  
...  

The endoplasmic reticulum (ER) is a central eukaryotic organelle with a tubular network made of hairpin proteins linked by hydrolysis of guanosine triphosphate nucleotides. Among posttranslational modifications initiated at the ER level, glycosylation is the most common reaction. However, our understanding of the impact of glycosylation on the ER structure remains unclear. Here, we show that exostosin-1 (EXT1) glycosyltransferase, an enzyme involved in N-glycosylation, is a key regulator of ER morphology and dynamics. We have integrated multiomics and superresolution imaging to characterize the broad effect of EXT1 inactivation, including the ER shape-dynamics-function relationships in mammalian cells. We have observed that inactivating EXT1 induces cell enlargement and enhances metabolic switches such as protein secretion. In particular, suppressing EXT1 in mouse thymocytes causes developmental dysfunctions associated with the ER network extension. Last, our data illuminate the physical and functional aspects of the ER proteome-glycome-lipidome structure axis, with implications in biotechnology and medicine.


2021 ◽  
Vol 220 (7) ◽  
Author(s):  
Tae Yeon Yoo ◽  
Timothy J. Mitchison

Macromolecular transport across the nuclear envelope depends on facilitated diffusion through nuclear pore complexes (NPCs). The interior of NPCs contains a permeability barrier made of phenylalanine-glycine (FG) repeat domains that selectively facilitates the permeation of cargoes bound to nuclear transport receptors (NTRs). FG-repeat domains in NPCs are a major site of O-linked N-acetylglucosamine (O-GlcNAc) modification, but the functional role of this modification in nucleocytoplasmic transport is unclear. We developed high-throughput assays based on optogenetic probes to quantify the kinetics of nuclear import and export in living human cells. We found that increasing O-GlcNAc modification of the NPC accelerated NTR-facilitated transport of proteins in both directions, and decreasing modification slowed transport. Superresolution imaging revealed strong enrichment of O-GlcNAc at the FG-repeat barrier. O-GlcNAc modification also accelerated passive permeation of a small, inert protein through NPCs. We conclude that O-GlcNAc modification accelerates nucleocytoplasmic transport by enhancing the nonspecific permeability of the FG-repeat barrier, perhaps by steric inhibition of interactions between FG repeats.


2021 ◽  
Author(s):  
Jinglin Zhang ◽  
Zhipeng Yang ◽  
Zhaoying Jia ◽  
Cong Bai

2021 ◽  
Vol 67 ◽  
pp. 77-83
Author(s):  
Li-An Chu ◽  
Shu-Wei Chang ◽  
Wei-Chun Tang ◽  
Yu-Ting Tseng ◽  
Peilin Chen ◽  
...  

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