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Journal articles on the topic 'Endosidin2'

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Author: Grafiati

Published: 10 December 2022

Last updated: 28 January 2023

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1

Zhang, Chunhua, Michelle Q. Brown, Wilhelmina van de Ven, Zhi-Min Zhang, Bin Wu, Michael C. Young, Lukáš Synek, et al. "Endosidin2 targets conserved exocyst complex subunit EXO70 to inhibit exocytosis." Proceedings of the National Academy of Sciences 113, no. 1 (November 25, 2015): E41—E50. http://dx.doi.org/10.1073/pnas.1521248112.

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The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.

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2

Huang, Lei, Xiaohui Li, Yang Li, Xianglin Yin, Yong Li, Bin Wu, Huaping Mo, et al. "Endosidin2-14 Targets the Exocyst Complex in Plants and Fungal Pathogens to Inhibit Exocytosis." Plant Physiology 180, no. 3 (May 9, 2019): 1756–70. http://dx.doi.org/10.1104/pp.18.01457.

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3

Zhao, Yujie, Xiaoting Hong, Xiong Chen, Chun Hu, Weihong Lu, Baoying Xie, Linhai Zhong, et al. "Deregulation of Exo70 Facilitates Innate and Acquired Cisplatin Resistance in Epithelial Ovarian Cancer by Promoting Cisplatin Efflux." Cancers 13, no. 14 (July 11, 2021): 3467. http://dx.doi.org/10.3390/cancers13143467.

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Whilst researches elucidating a diversity of intracellular mechanisms, platinum-resistant epithelial ovarian cancer (EOC) remains a major challenge in the treatment of ovarian cancer. Here we report that Exo70, a key subunit of the exocyst complex, contributes to both innate and acquired cisplatin resistance of EOC. Upregulation of Exo70 is observed in EOC tissues and is related to platinum resistance and progression-free survival of EOC patients. Exo70 suppressed the cisplatin sensitivity of EOC cells through promoting exocytosis-mediated efflux of cisplatin. Moreover, cisplatin-induced autophagy-lysosomal degradation of Exo70 protein by modulating phosphorylation of AMPK and mTOR, thereby reducing the cellular resistance. However, the function was hampered during prolonged cisplatin treatment, which in turn stabilized Exo70 to facilitate the acquired cisplatin resistance of EOC cells. Knockdown of Exo70, or inhibiting exocytosis by Exo70 inhibitor Endosidin2, reversed the cisplatin resistance of EOC cells both in vitro and in vivo. Our results suggest that Exo70 overexpression and excessive stability contribute to innate and acquired cisplatin resistance through the increase in cisplatin efflux, and targeting Exo70 might be an approach to overcome cisplatin resistance in EOC treatment.

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4

Sharda, Anish V., Alexandra M. Barr, Joshua A. Harrison, Adrian R. Wilkie, Chao Fang, Lourdes M. Mendez, Ionita C. Ghiran, Joseph E. Italiano, and Robert Flaumenhaft. "VWF maturation and release are controlled by 2 regulators of Weibel-Palade body biogenesis: exocyst and BLOC-2." Blood 136, no. 24 (December 10, 2020): 2824–37. http://dx.doi.org/10.1182/blood.2020005300.

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Abstract von Willebrand factor (VWF) is an essential hemostatic protein that is synthesized in endothelial cells and stored in Weibel-Palade bodies (WPBs). Understanding the mechanisms underlying WPB biogenesis and exocytosis could enable therapeutic modulation of endogenous VWF, yet optimal targets for modulating VWF release have not been established. Because biogenesis of lysosomal related organelle-2 (BLOC-2) functions in the biogenesis of platelet dense granules and melanosomes, which like WPBs are lysosome-related organelles, we hypothesized that BLOC-2–dependent endolysosomal trafficking is essential for WPB biogenesis and sought to identify BLOC-2–interacting proteins. Depletion of BLOC-2 caused misdirection of cargo-carrying transport tubules from endosomes, resulting in immature WPBs that lack endosomal input. Immunoprecipitation of BLOC-2 identified the exocyst complex as a binding partner. Depletion of the exocyst complex phenocopied BLOC-2 depletion, resulting in immature WPBs. Furthermore, releasates of immature WPBs from either BLOC-2 or exocyst-depleted endothelial cells lacked high-molecular weight (HMW) forms of VWF, demonstrating the importance of BLOC-2/exocyst-mediated endosomal input during VWF maturation. However, BLOC-2 and exocyst showed very different effects on VWF release. Although BLOC-2 depletion impaired exocytosis, exocyst depletion augmented WPB exocytosis, indicating that it acts as a clamp. Exposure of endothelial cells to a small molecule inhibitor of exocyst, Endosidin2, reversibly augmented secretion of mature WPBs containing HMW forms of VWF. These studies show that, although BLOC-2 and exocyst cooperate in WPB formation, only exocyst serves to clamp WPB release. Exocyst function in VWF maturation and release are separable, a feature that can be exploited to enhance VWF release.

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5

Wilkop, Thomas E., Minmin Wang, Angelo Heringer, Jaideep Singh, Florence Zakharov, Viswanathan V. Krishnan, and Georgia Drakakaki. "NMR spectroscopy analysis reveals differential metabolic responses in arabidopsis roots and leaves treated with a cytokinesis inhibitor." PLOS ONE 15, no. 11 (November 6, 2020): e0241627. http://dx.doi.org/10.1371/journal.pone.0241627.

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In plant cytokinesis, de novo formation of a cell plate evolving into the new cell wall partitions the cytoplasm of the dividing cell. In our earlier chemical genomics studies, we identified and characterized the small molecule endosidin-7, that specifically inhibits callose deposition at the cell plate, arresting late-stage cytokinesis in arabidopsis. Endosidin-7 has emerged as a very valuable tool for dissecting this essential plant process. To gain insights regarding its mode of action and the effects of cytokinesis inhibition on the overall plant response, we investigated the effect of endosidin-7 through a nuclear magnetic resonance spectroscopy (NMR) metabolomics approach. In this case study, metabolomics profiles of arabidopsis leaf and root tissues were analyzed at different growth stages and endosidin-7 exposure levels. The results show leaf and root-specific metabolic profile changes and the effects of endosidin-7 treatment on these metabolomes. Statistical analyses indicated that the effect of endosidin-7 treatment was more significant than the developmental impact. The endosidin-7 induced metabolic profiles suggest compensations for cytokinesis inhibition in central metabolism pathways. This study further shows that long-term treatment of endosidin-7 profoundly changes, likely via alteration of hormonal regulation, the primary metabolism of arabidopsis seedlings. Hormonal pathway-changes are likely reflecting the plant’s responses, compensating for the arrested cell division, which in turn are leading to global metabolite modulation. The presented NMR spectral data are made available through the Metabolomics Workbench, providing a reference resource for the scientific community.

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6

Lockhart, Jennifer. "Endosidin20: A Key to Unlock the Secrets of Cellulose Biosynthesis." Plant Cell 32, no. 7 (May 14, 2020): 2061–62. http://dx.doi.org/10.1105/tpc.20.00382.

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7

Huang, Lei, Xiaohui Li, and Chunhua Zhang. "Endosidin20‐1 is more potent than endosidin20 in inhibiting plant cellulose biosynthesis and molecular docking analysis of cellulose biosynthesis inhibitors on modeled cellulose synthase structure." Plant Journal 106, no. 6 (April 21, 2021): 1605–24. http://dx.doi.org/10.1111/tpj.15258.

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8

Huang, Lei, Xiaohui Li, Weiwei Zhang, Nolan Ung, Nana Liu, Xianglin Yin, Yong Li, et al. "Endosidin20 Targets the Cellulose Synthase Catalytic Domain to Inhibit Cellulose Biosynthesis." Plant Cell 32, no. 7 (April 23, 2020): 2141–57. http://dx.doi.org/10.1105/tpc.20.00202.

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9

Huang, Lei, and Chunhua Zhang. "Endosidin20 does not affect cellulose synthase complex transport from ER to the Golgi." Plant Signaling & Behavior 15, no. 8 (June 21, 2020): 1780039. http://dx.doi.org/10.1080/15592324.2020.1780039.

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10

Park, Eunsook, Sara M. Díaz-Moreno, Destiny J. Davis, Thomas E. Wilkop, Vincent Bulone, and Georgia Drakakaki. "Endosidin 7 Specifically Arrests Late Cytokinesis and Inhibits Callose Biosynthesis, Revealing Distinct Trafficking Events during Cell Plate Maturation." Plant Physiology 165, no. 3 (May 23, 2014): 1019–34. http://dx.doi.org/10.1104/pp.114.241497.

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11

Lešková, Alexandra, Mária Labajová, Miroslav Krausko, Alexandra Zahradníková, František Baluška, Karol Mičieta, Ján Turňa, and Ján Jásik. "Endosidin 2 accelerates PIN2 endocytosis and disturbs intracellular trafficking of PIN2, PIN3, and PIN4 but not of SYT1." PLOS ONE 15, no. 8 (August 13, 2020): e0237448. http://dx.doi.org/10.1371/journal.pone.0237448.

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12

Robert, S., S. N. Chary, G. Drakakaki, S. Li, Z. Yang, N. V. Raikhel, and G. R. Hicks. "Endosidin1 defines a compartment involved in endocytosis of the brassinosteroid receptor BRI1 and the auxin transporters PIN2 and AUX1." Proceedings of the National Academy of Sciences 105, no. 24 (June 11, 2008): 8464–69. http://dx.doi.org/10.1073/pnas.0711650105.

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13

Kania, Urszula, Tomasz Nodzyński, Qing Lu, Glenn R. Hicks, Wim Nerinckx, Kiril Mishev, François Peurois, et al. "The Inhibitor Endosidin 4 Targets SEC7 Domain-Type ARF GTPase Exchange Factors and Interferes with Subcellular Trafficking in Eukaryotes." Plant Cell 30, no. 10 (July 17, 2018): 2553–72. http://dx.doi.org/10.1105/tpc.18.00127.

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14

Davis, Destiny J., Minmin Wang, Iben Sørensen, Jocelyn K. C. Rose, David S. Domozych, and Georgia Drakakaki. "Callose deposition is essential for the completion of cytokinesis in the unicellular alga Penium margaritaceum." Journal of Cell Science 133, no. 19 (September 7, 2020): jcs249599. http://dx.doi.org/10.1242/jcs.249599.

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ABSTRACTCytokinesis in land plants involves the formation of a cell plate that develops into the new cell wall. Callose, a β-1,3 glucan, accumulates at later stages of cell plate development, presumably to stabilize this delicate membrane network during expansion. Cytokinetic callose is considered specific to multicellular plant species, because it has not been detected in unicellular algae. Here we present callose at the cytokinesis junction of the unicellular charophyte, Penium margaritaceum. Callose deposition at the division plane of P. margaritaceum showed distinct, spatiotemporal patterns likely representing distinct roles of this polymer in cytokinesis. Pharmacological inhibition of callose deposition by endosidin 7 resulted in cytokinesis defects, consistent with the essential role for this polymer in P. margaritaceum cell division. Cell wall deposition at the isthmus zone was also affected by the absence of callose, demonstrating the dynamic nature of new wall assembly in P. margaritaceum. The identification of candidate callose synthase genes provides molecular evidence for callose biosynthesis in P. margaritaceum. The evolutionary implications of cytokinetic callose in this unicellular zygnematopycean alga is discussed in the context of the conquest of land by plants.This article has an associated First Person interview with the first author of the paper.

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15

Qi, Xingyun, and Huanquan Zheng. "Rab-A1c GTPase Defines a Population of the Trans-Golgi Network that Is Sensitive to Endosidin1 during Cytokinesis in Arabidopsis." Molecular Plant 6, no. 3 (May 2013): 847–59. http://dx.doi.org/10.1093/mp/sss116.

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16

Davis, Destiny J., Stephen C. McDowell, Eunsook Park, Glenn Hicks, Thomas E. Wilkop, and Georgia Drakakaki. "The RAB GTPase RABA1e localizes to the cell plate and shows distinct subcellular behavior from RABA2a under Endosidin 7 treatment." Plant Signaling & Behavior 11, no. 3 (April 1, 2015): e984520. http://dx.doi.org/10.4161/15592324.2014.984520.

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17

Doyle, Siamsa M., Ash Haeger, Thomas Vain, Adeline Rigal, Corrado Viotti, Małgorzata Łangowska, Qian Ma, et al. "An early secretory pathway mediated by GNOM-LIKE 1 and GNOM is essential for basal polarity establishment in Arabidopsis thaliana." Proceedings of the National Academy of Sciences 112, no. 7 (February 2, 2015): E806—E815. http://dx.doi.org/10.1073/pnas.1424856112.

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Spatial regulation of the plant hormone indole-3-acetic acid (IAA, or auxin) is essential for plant development. Auxin gradient establishment is mediated by polarly localized auxin transporters, including PIN-FORMED (PIN) proteins. Their localization and abundance at the plasma membrane are tightly regulated by endomembrane machinery, especially the endocytic and recycling pathways mediated by the ADP ribosylation factor guanine nucleotide exchange factor (ARF-GEF) GNOM. We assessed the role of the early secretory pathway in establishing PIN1 polarity in Arabidopsis thaliana by pharmacological and genetic approaches. We identified the compound endosidin 8 (ES8), which selectively interferes with PIN1 basal polarity without altering the polarity of apical proteins. ES8 alters the auxin distribution pattern in the root and induces a strong developmental phenotype, including reduced root length. The ARF-GEF–defective mutants gnom-like 1 (gnl1-1) and gnom (van7) are significantly resistant to ES8. The compound does not affect recycling or vacuolar trafficking of PIN1 but leads to its intracellular accumulation, resulting in loss of PIN1 basal polarity at the plasma membrane. Our data confirm a role for GNOM in endoplasmic reticulum (ER)–Golgi trafficking and reveal that a GNL1/GNOM-mediated early secretory pathway selectively regulates PIN1 basal polarity establishment in a manner essential for normal plant development.

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18

Fujimoto, Brent A., Madison Young, Lamar Carter, Alina P. S. Pang, Michael J. Corley, Ben Fogelgren, and Noemi Polgar. "The exocyst complex regulates insulin-stimulated glucose uptake of skeletal muscle cells." American Journal of Physiology-Endocrinology and Metabolism 317, no. 6 (December 1, 2019): E957—E972. http://dx.doi.org/10.1152/ajpendo.00109.2019.

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Skeletal muscle handles ~80–90% of the insulin-induced glucose uptake. In skeletal muscle, insulin binding to its cell surface receptor triggers redistribution of intracellular glucose transporter GLUT4 protein to the cell surface, enabling facilitated glucose uptake. In adipocytes, the eight-protein exocyst complex is an indispensable constituent in insulin-induced glucose uptake, as it is responsible for the targeted trafficking and plasma membrane-delivery of GLUT4. However, the role of the exocyst in skeletal muscle glucose uptake has never been investigated. Here we demonstrate that the exocyst is a necessary factor in insulin-induced glucose uptake in skeletal muscle cells as well. The exocyst complex colocalizes with GLUT4 storage vesicles in L6-GLUT4myc myoblasts at a basal state and associates with these vesicles during their translocation to the plasma membrane after insulin signaling. Moreover, we show that the exocyst inhibitor endosidin-2 and a heterozygous knockout of Exoc5 in skeletal myoblast cells both lead to impaired GLUT4 trafficking to the plasma membrane and hinder glucose uptake in response to an insulin stimulus. Our research is the first to establish that the exocyst complex regulates insulin-induced GLUT4 exocytosis and glucose metabolism in muscle cells. A deeper knowledge of the role of the exocyst complex in skeletal muscle tissue may help our understanding of insulin resistance in type 2 diabetes.

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19

Tóth, Réka, Claas Gerding-Reimers, Michael J. Deeks, Sascha Menninger, Rafael M. Gallegos, Isabella A. N. Tonaco, Katja Hübel, Patrick J. Hussey, Herbert Waldmann, and George Coupland. "Prieurianin/endosidin 1 is an actin-stabilizing small molecule identified from a chemical genetic screen for circadian clock effectors in Arabidopsis thaliana." Plant Journal 71, no. 2 (June 28, 2012): 338–52. http://dx.doi.org/10.1111/j.1365-313x.2012.04991.x.

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20

Rodriguez-Furlan, Cecilia, David Domozych, Weixing Qian, Per-Anders Enquist, Xiaohui Li, Chunhua Zhang, Rolf Schenk, et al. "Interaction between VPS35 and RABG3f is necessary as a checkpoint to control fusion of late compartments with the vacuole." Proceedings of the National Academy of Sciences 116, no. 42 (September 30, 2019): 21291–301. http://dx.doi.org/10.1073/pnas.1905321116.

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Vacuoles are essential organelles in plants, playing crucial roles, such as cellular material degradation, ion and metabolite storage, and turgor maintenance. Vacuoles receive material via the endocytic, secretory, and autophagic pathways. Membrane fusion is the last step during which prevacuolar compartments (PVCs) and autophagosomes fuse with the vacuole membrane (tonoplast) to deliver cargoes. Protein components of the canonical intracellular fusion machinery that are conserved across organisms, including Arabidopsis thaliana, include complexes, such as soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs), that catalyze membrane fusion, and homotypic fusion and vacuole protein sorting (HOPS), that serve as adaptors which tether cargo vesicles to target membranes for fusion under the regulation of RAB-GTPases. The mechanisms regulating the recruitment and assembly of tethering complexes are not well-understood, especially the role of RABs in this dynamic regulation. Here, we report the identification of the small synthetic molecule Endosidin17 (ES17), which interferes with synthetic, endocytic, and autophagic traffic by impairing the fusion of late endosome compartments with the tonoplast. Multiple independent target identification techniques revealed that ES17 targets the VPS35 subunit of the retromer tethering complex, preventing its normal interaction with the Arabidopsis RAB7 homolog RABG3f. ES17 interference with VPS35–RABG3f interaction prevents the retromer complex to endosome anchoring, resulting in retention of RABG3f. Using multiple approaches, we show that VPS35–RABG3f–GTP interaction is necessary to trigger downstream events like HOPS complex assembly and fusion of late compartments with the tonoplast. Overall, our results support a role for the interaction of RABG3f–VPS35 as a checkpoint in the control of traffic toward the vacuole.

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21

Sharda, Anish V., Joshua Harrison, Adrian R. Wilkie, Chao Fang, Lourdes M. Mendez, Joseph E. Italiano, and Robert C. Flaumenhaft. "VWF Exocytosis and Biogenesis of Weibel Palade Bodies in Endothelial Cells Are Differentially Controlled By Interactions between Bloc-2 and the Exocyst Complex." Blood 134, Supplement_1 (November 13, 2019): 8. http://dx.doi.org/10.1182/blood-2019-127712.

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von Willebrand factor (vWF) is an essential plasma hemostatic factor that also participates in pathophysiologic processes such as thrombosis, angiogenesis and tumor metastasis. vWF is synthesized in endothelial cells and stored in specialized granules, Weibel-Palade bodies (WPBs), which exhibit characteristics of secretory granules termed lysosomal-related organelles (LROs). Understanding the mechanisms underlying WPB biogenesis and vWF exocytosis could enable therapeutic modulation of endogenous vWF; however, fundamental aspects of vWF trafficking mechanisms remain unknown. Since biogenesis of lysosomal related organelle 2 (BLOC-2), a complex of HPS3, HPS5 and HPS6 proteins, functions in biogenesis of other LROs such as platelet dense granules and melanosomes, we hypothesized that BLOC-2-dependent endolysosomal trafficking was essential for WPB biogenesis. BLOC-2 was depleted in human umbilical vein endothelial cells (HUVECs) by transduction of cells with lentiviral particles containing HPS6 shRNA. Evaluation of WPBs using multicolor immunofluorescence microscopy showed that the WPBs were immature, granular and abnormally localized to the perinuclear space, as compared to mature, linear-shaped WPBs, distributed peripherally in control cells (number of WPBs > 1.5 µm per cell, HPS6 3±2 vs. control 16±6). Immature WPBs in BLOC-2-depleted HUVECs lacked expression of endosome-derived cargo CD63, but not P-selectin, a synthetic cargo that enters WPBs at the trans-Golgi network. Live cell imaging showed that when BLOC-2 was depleted from HUVECs expressing CD63-GFP, CD63-GFP no longer trafficked to WPBs. Instead, endosome-derived transport tubules were mistargeted to the core of the cell. In comparison, CD63-GFP labeled WPBs intensely in control cells, where direct interaction between endosome-derived transport tubules and WPBs was evident. To identify binding partners of BLOC-2 that facilitate targeting of endosome-derived transport tubules to maturing WPBs, we performed immunoprecipitation of endogenous BLOC-2 in HUVEC lysates and evaluated the captured proteins using mass spectrometry. Several components of the exocyst complex, namely EXOC2, EXOC4 and EXO70, were enriched in BLOC-2 immunoprecipitates. This interaction was confirmed by reciprocal co-immunoprecipitation experiments with HPS6 and EXOC4. Evaluation by immunogold electron microscopy showed that EXOC4 colocalized with HPS6 in HUVECs. EXOC4 depletion using targeted siRNA resulted in WPBs that were immature, granular-appearing and perinuclearly localized, similar to BLOC-2-depleted HUVECs (number of WPBs > 1.5 µm per cell, EXOC4 3±2.5 vs. control 16±5). Overall, these observations indicate that both BLOC-2 and the exocyst complex are critical for endolysosomal trafficking involved in WPB maturation. We next evaluated the roles of BLOC-2 and the exocyst complex in vWF exocytosis. Depletion of BLOC-2 from HUVECs resulted in a 63±3% decrease in thrombin-induced vWF exocytosis and a 41±4% decrease in constitutive vWF exocytosis. Multimer analysis showed loss of high-molecular weight vWF multimers. In vivo studies showed that vWF exocytosis following systemic epinephrine infusion was 158±12% of basal levels in WT mice compared 100±20% in HPS6-/-mice, indicating lack of agonist-induced vWF release in BLOC-2 depleted mice. To evaluate the role of the exocyst complex in vWF release, both EXOC4 and EXO70 were depleted from HUVECS using siRNA. Unexpectedly, depletion of either exocyst complex component augmented thrombin-induced vWF exocytosis (EXOC4 105±21%; EXO70 99±22%). Similarly, endosidin 2, a small molecule inhibitor of EXO70, also augmented vWF exocytosis by 122±26%. These studies demonstrate that both BLOC-2 and the exocyst complex contribute to WPB biogenesis, perhaps working together based on their binding and colocalization on WBPs. However, these two complexes have opposing effects on vWF secretion. While BLOC-2 is necessary for vWF secretion, the exocyst suppresses release. Disclosures Italiano: Platelet Biogenesis: Employment, Equity Ownership; Ionis Research Funding: Research Funding. Flaumenhaft:PlateletDiagnostics: Consultancy, Other: Founder; Relay Therapeutics: Consultancy.

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22

An, Seong J., Alexander Anneken, Zhiqun Xi, Changseon Choi, Joseph Schlessinger, and Derek Toomre. "Regulation of EGF-stimulated activation of the PI-3K/AKT pathway by exocyst-mediated exocytosis." Proceedings of the National Academy of Sciences 119, no. 48 (November 23, 2022). http://dx.doi.org/10.1073/pnas.2208947119.

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The phosphoinositide-3 kinase (PI-3K)/AKT cell survival pathway is an important pathway activated by EGFR signaling. Here we show, that in addition to previously described critical components of this pathway, i.e., the docking protein Gab1, the PI-3K/AKT pathway in epithelial cells is regulated by the exocyst complex, which is a vesicle tether that is essential for exocytosis. Using live-cell imaging, we demonstrate that PI(3,4,5)P 3 levels fluctuate at the membrane on a minutes time scale and that these fluctuations are associated with local PI(3,4,5)P 3 increases at sites where recycling vesicles undergo exocytic fusion. Supporting a role for exocytosis in PI(3,4,5)P 3 generation, acute promotion of exocytosis by optogenetically driving exocyst-mediated vesicle tethering up-regulates PI(3,4,5)P 3 production and AKT activation. Conversely, acute inhibition of exocytosis using Endosidin2, a small-molecule inhibitor of the exocyst subunit Exo70 (also designated EXOC7), or inhibition of exocyst function by siRNA-mediated knockdown of the exocyst subunit Sec15 (EXOC6), impairs PI(3,4,5)P 3 production and AKT activation induced by EGF stimulation of epithelial cells. Moreover, prolonged inhibition of EGF signaling by EGFR tyrosine kinase inhibitors results in spontaneous reactivation of AKT without a concomitant relief of EGFR inhibition. However, this reactivation can be negated by acutely inhibiting the exocyst. These experiments demonstrate that exocyst-mediated exocytosis—by regulating PI(3,4,5)P 3 levels at the plasma membrane—subserves activation of the PI-3K/AKT pathway by EGFR in epithelial cells.

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23

Huang, Lei, and Chunhua Zhang. "The Mode of Action of Endosidin20 Differs from That of Other Cellulose Biosynthesis Inhibitors." Plant and Cell Physiology, October 26, 2020. http://dx.doi.org/10.1093/pcp/pcaa136.

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Abstract Endosidin20 (ES20) was recently identified as a cellulose biosynthesis inhibitor (CBI) that targets the catalytic domain of CELLULOSE SYNTHASE 6 (CESA6) and thus inhibits the growth of Arabidopsis thaliana. Here, we characterized the effects of ES20 on the growth of other plant species and found that ES20 is a broad-spectrum plant growth inhibitor. We tested the inhibitory effects of previously characterized CBIs (isoxaben, indaziflam and C17) on the growth of Arabidopsis cesa6 mutants that have reduced sensitivity to ES20. We found that most of these mutants are sensitive to isoxaben, indaziflam and C17, indicating that these tested CBIs have a different mode of action than ES20. ES20 also has a synergistic inhibitory effect on plant growth when jointly applied with other CBIs, further confirming that ES20 has a different mode of action than isoxaben, indaziflam and C17. We demonstrated that plants carrying two missense mutations conferring resistance to ES20 and isoxaben can tolerate the dual inhibitory effects of these CBIs when combined. ES20 inhibits Arabidopsis growth in growth medium and in soil following direct spraying. Therefore, our results pave the way for using ES20 as a broad-spectrum herbicide, and for the use of gene-editing technologies to produce ES20-resistant crop plants.

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24

Yao, Yi, Kalpana Subedi, Tingting Liu, Namir Khalasawi, Carla Diana Pretto-Kernahan, Jesse William Wotring, Jie Wang, et al. "Surface translocation of ACE2 and TMPRSS2 upon TLR4/7/8 activation is required for SARS-CoV-2 infection in circulating monocytes." Cell Discovery 8, no. 1 (September 9, 2022). http://dx.doi.org/10.1038/s41421-022-00453-8.

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AbstractInfection of human peripheral blood cells by SARS-CoV-2 has been debated because immune cells lack mRNA expression of both angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease type 2 (TMPRSS2). Herein we demonstrate that resting primary monocytes harbor abundant cytoplasmic ACE2 and TMPRSS2 protein and that circulating exosomes contain significant ACE2 protein. Upon ex vivo TLR4/7/8 stimulation, cytoplasmic ACE2 was quickly translocated to the monocyte cell surface independently of ACE2 transcription, while TMPRSS2 surface translocation occurred in conjunction with elevated mRNA expression. The rapid translocation of ACE2 to the monocyte cell surface was blocked by the endosomal trafficking inhibitor endosidin 2, suggesting that endosomal ACE2 could be derived from circulating ACE2-containing exosomes. TLR-stimulated monocytes concurrently expressing ACE2 and TMPRSS2 on the cell surface were efficiently infected by SARS-CoV-2, which was significantly mitigated by remdesivir, TMPRSS2 inhibitor camostat, and anti-ACE2 antibody. Mass cytometry showed that ACE2 surface translocation in peripheral myeloid cells from patients with severe COVID-19 correlated with its hyperactivation and PD-L1 expression. Collectively, TLR4/7/8-induced ACE2 translocation with TMPRSS2 expression makes circulating monocytes permissive to SARS-CoV-2 infection.

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