Effect of tolytoxin on tunneling nanotube formation and function

Senol, Aysegul Dilsizoglu; Pepe, Anna; Grudina, Clara; Sassoon, Nathalie; Ueoka, Ryoko; Bousset, Luc; Melki, Ronald; Piel, Jörn; Gugger, Muriel; Zurzolo, Chiara

doi:10.1038/s41598-019-42161-6

Cited by 39 publications

(33 citation statements)

References 51 publications

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“…Despite detection of different inhibitory compounds, the specific TNT inhibitors are still not developed 20 . Different strategies to inhibit TNTs formation and function are proposed, including those inhibiting microfilament formation 67 , mTOR pathway or vesicular transport controlled by the small Rab GTPases 68 . This data rather suggest that there are multiple TNT formation pathways, which are selectively expressed depending on cellular context 20 .…”

Section: Discussionmentioning

confidence: 99%

Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells

et al. 2019

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Intercellular communication within the bone marrow niche significantly promotes leukemogenesis and provides protection of leukemic cells from therapy. Secreted factors, intercellular transfer of mitochondria and the receptor–ligand interactions have been shown as mediators of this protection. Here we report that tunneling nanotubes (TNTs)—long, thin membranous structures, which have been identified as a novel mode of intercellular cross-talk—are formed in the presence of stroma and mediate transfer of cellular vesicles from stroma to leukemic cells. Importantly, transmission of vesicles via TNTs from stromal cells increases resistance of leukemic cells to the tyrosine kinase inhibitor, imatinib. Using correlative light-electron microscopy and electron tomography we show that stromal TNTs contain vesicles, provide membrane continuity with the cell bodies and can be open-ended. Moreover, trans-SILAC studies to reveal the non-autonomous proteome showed that specific sets of proteins are transferred together with cellular vesicles from stromal to leukemic cells, with a potential role in survival and adaptation. Altogether, our findings provide evidence for the biological role of the TNT-mediated vesicle exchange between stromal and leukemic cells, implicating the direct vesicle and protein transfer in the stroma-provided protection of leukemic cells.

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Section: Discussionmentioning

confidence: 99%

Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells

et al. 2019

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“…As described before 20 , confluent CAD cells were mechanically detached and counted, and 300,000 cells were plated for 6 h per well in a 6 well plate. Cells were transfected as described above, using the abovementioned plasmids.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were then incubated for permeabilization and blocking with 2% BSA including 0.0075% saponin at RT for 1 h. Primary monoclonal antibody of vinculin (Sigma, 1:500) was prepared in PBS having 2% BSA and 0.01% saponin and incubated at RT for 1 h. After several washes with PBS cells were incubated with secondary antibody goat anti-mouse Alexa Fluor 546 (Invitrogen, Thermo Fisher Scientific) in the same solution at RT for 1 h. Cells were then stained with HCS Cell Mask Blue Stain (Invitrogen, Thermo Fisher Scientific, 1:5000) in PBS for 20 min, washed several times and mounted. Quantification was performed as described before 20 , 30 , 32 by (1) creating the ROI restricted to the outer region of the cells that covers only attached filopodia; (2) automatized counting of the vinculin positive filopodia using spot detector tool (ICY software).…”

Section: Methodsmentioning

confidence: 99%

“…They were shown to be hijacked and utilized as means of transport by different pathogens, such as viruses like HIV 15 , 16 , and bacteria 17 . Interestingly, TNTs have been shown to be involved in spreading of amyloid proteins such as prions 18 , alpha synuclein 19 , 20 , huntingtin 21 etc. from diseased to healthy neighbouring cells, and therefore suggested to have a role in the progression of different neurodegenerative diseases 22 .…”

Section: Introductionmentioning

confidence: 99%

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Rab35 and its effectors promote formation of tunneling nanotubes in neuronal cells

Bhat

Ljubojevic

Zhu

et al. 2020

Sci Rep

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Tunneling nanotubes (TNTs) are F-actin rich structures that connect distant cells, allowing the transport of many cellular components, including vesicles, organelles and molecules. Rab GTPases are the major regulators of vesicle trafficking and also participate in actin cytoskeleton remodelling, therefore, we examined their role in TNTs. Rab35 functions with several proteins that are involved in vesicle trafficking such as ACAP2, MICAL-L1, ARF6 and EHD1, which are known to be involved in neurite outgrowth. Here we show that Rab35 promotes TNT formation and TNT-mediated vesicle transfer in a neuronal cell line. Furthermore, our data indicates that Rab35-GTP, ACAP2, ARF6-GDP and EHD1 act in a cascade mechanism to promote TNT formation. Interestingly, MICAL-L1 overexpression, shown to be necessary for the action of Rab35 on neurite outgrowth, showed no effect on TNTs, indicating that TNT formation and neurite outgrowth may be processed through similar but not identical pathways, further supporting the unique identity of these cellular protrusions.

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“…Comparing the efforts that promote TNT formation, the development of TNT inhibitors seems more feasible. Actin inhibitors (e.g., cytochalasin, latrunculin, and tolytoxin) have been widely used in in vitro studies [ 10 , 34 , 82 , 143 ]. However, these compounds cannot be applied as medicine due to their cytotoxic effect on the cellular cytoskeleton in tissues [ 144 , 145 ].…”

Section: Tnts As Potential Therapeutic Targetsmentioning

confidence: 99%

Opportunities and Challenges in Tunneling Nanotubes Research: How Far from Clinical Application?

Han

Wang

2021

IJMS

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Tunneling nanotubes (TNTs) are recognized long membrane nanotubes connecting distance cells. In the last decade, growing evidence has shown that these subcellular structures mediate the specific transfer of cellular materials, pathogens, and electrical signals between cells. As intercellular bridges, they play a unique role in embryonic development, collective cell migration, injured cell recovery, cancer treatment resistance, and pathogen propagation. Although TNTs have been considered as potential drug targets for treatment, there is still a long way to go to translate the research findings into clinical practice. Herein, we emphasize the heterogeneous nature of TNTs by systemically summarizing the current knowledge on their morphology, structure, and biogenesis in different types of cells. Furthermore, we address the communication efficiency and biological outcomes of TNT-dependent transport related to diseases. Finally, we discuss the opportunities and challenges of TNTs as an exciting therapeutic approach by focusing on the development of efficient and safe drugs targeting TNTs.

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Effect of tolytoxin on tunneling nanotube formation and function

Cited by 39 publications

References 51 publications

Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells

Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells

Rab35 and its effectors promote formation of tunneling nanotubes in neuronal cells

Opportunities and Challenges in Tunneling Nanotubes Research: How Far from Clinical Application?

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