<scp>SKIP</scp>
            ‐
            <scp>HOPS</scp>
            recruits
            <scp>TBC</scp>
            1D15 for a Rab7‐to‐Arl8b identity switch to control late endosome transport

Jongsma, Marlieke L.M.; Bakker, Jeroen; Cabukusta, Birol; Liv, Nalan; Elsland, Daphne M. van; Fermie, Job; Akkermans, Jimmy Ll; Kuijl, Coenraad; Zanden, Sabina Y. van der; Janssen, Lennert; Hoogzaad, Denise; Kant, Rik van der; Wijdeven, Ruud H.; Klumperman, Judith; Berlin, Ilana; Neefjes, Jacques

doi:10.15252/embj.2019102301

Cited by 65 publications

(62 citation statements)

References 92 publications

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“…First, we cultured CAD cells transiently transfected with a plasmid encoding LAMP1-GFP and loaded with Alexa 568-tagged α-syn fibrils on gridded coverslips and imaged α-syn fibril-treated cells in FM while marking coordinates of α-syn positive (Alexa568+/GFP+) and negative (Alexa568−/GFP+) LAMP1-GFP lysosomes. Following FM imaging, the CAD cells were prepared for EM by keeping their orientation, and serial sections were collected from the region containing the previously marked coordinates (see also Materials and methods) [75,76]. Then, the FM signal was correlated with EM images.…”

Section: α-Syn Fibrils Affect the Morphology And Function Of Lysosomesmentioning

confidence: 99%

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

et al. 2021

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The accumulation of α-synuclein (α-syn) aggregates in specific brain regions is a hallmark of synucleinopathies including Parkinson disease (PD). α-Syn aggregates propagate in a “prion-like” manner and can be transferred inside lysosomes to recipient cells through tunneling nanotubes (TNTs). However, how lysosomes participate in the spreading of α-syn aggregates is unclear. Here, by using super-resolution (SR) and electron microscopy (EM), we find that α-syn fibrils affect the morphology of lysosomes and impair their function in neuronal cells. In addition, we demonstrate that α-syn fibrils induce peripheral redistribution of lysosomes, likely mediated by transcription factor EB (TFEB), increasing the efficiency of α-syn fibrils’ transfer to neighboring cells. We also show that lysosomal membrane permeabilization (LMP) allows the seeding of soluble α-syn in cells that have taken up α-syn fibrils from the culture medium, and, more importantly, in healthy cells in coculture, following lysosome-mediated transfer of the fibrils. Moreover, we demonstrate that seeding occurs mainly at lysosomes in both donor and acceptor cells, after uptake of α-syn fibrils from the medium and following their transfer, respectively. Finally, by using a heterotypic coculture system, we determine the origin and nature of the lysosomes transferred between cells, and we show that donor cells bearing α-syn fibrils transfer damaged lysosomes to acceptor cells, while also receiving healthy lysosomes from them. These findings thus contribute to the elucidation of the mechanism by which α-syn fibrils spread through TNTs, while also revealing the crucial role of lysosomes, working as a Trojan horse for both seeding and propagation of disease pathology.

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Section: α-Syn Fibrils Affect the Morphology And Function Of Lysosomesmentioning

confidence: 99%

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

et al. 2021

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“…In this regard, RUFY3/4 and RILP function as dynein-dynactin adaptors for populations of endolysosomes decorated with ARL8 and RAB7, respectively (Jongsma et al, 2020). Finally, different dynein-dynactin adaptors could participate in a sequential handoff mechanism, as recently reported for the retrograde transport of maturing autophagosomes in the axon (Cason et al, 2020).…”

Section: Discussionmentioning

confidence: 64%

RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Keren-Kaplan¹,

Sarić²,

Ghosh³

et al. 2021

Preprint

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The small GTPase ARL8 associates with lysosomes and recruits several effectors that mediate coupling to kinesins for anterograde transport, as well as tethering for eventual fusion with other organelles. Herein we report the identification of the “RUN- and FYVE-domain-containing” proteins RUFY3 and RUFY4 as novel ARL8 effectors that couple lysosomes to dynein-dynactin for retrograde transport. Using various biochemical approaches, we find that RUFY3/4 interact with both GTP-bound ARL8 and dynein-dynactin. In addition, we show that RUFY3/4 are both necessary and sufficient for concentration of lysosomes in the juxtanuclear area of the cell. RUFY3/4 also promote retrograde transport of lysosomes in the axon of hippocampal neurons. The function of RUFY3/4 in retrograde transport is required for juxtanuclear redistribution of lysosomes upon serum starvation or cytoplasmic alkalinization, and may underlie the reported roles of RUFY3/4 in axon development/degeneration, cancer and immunity. These studies thus establish RUFY3/4 as novel ARL8-dependent, dynein-dynactin adaptors, and highlight the role of ARL8 in the regulation of both anterograde and retrograde lysosome transport.

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“…Lysosomes receive input from the endocytic, autophagic, phagocytic and trans-Golgi network pathways while they traffic throughout the cell (Saftig & Klumperman, 2009). They interact with other lysosomes and endosomes via kiss-and-run events or membrane fusion, resulting in the exchange of membranes and content (Huotari & Helenius, 2011; M. L. Jongsma et al, 2020; Pols et al, 2013).…”

Section: Resultsmentioning

confidence: 99%

Correlative Organelle Microscopy: fluorescence guided volume electron microscopy of intracellular processes

Loginov

Fermie

Fokkema

et al. 2021

Preprint

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Intracellular processes depend on a strict spatial and temporal organization of proteins and organelles. Directly linking molecular to nanoscale ultrastructural information is therefore crucial to understand cellular physiology. Volume or 3-dimensional (3D) correlative light and electron microscopy (volume-CLEM) holds unique potential to explore cellular physiology at high-resolution ultrastructural detail across cell volumes. Application of volume-CLEM is however hampered by limitations in throughput and 3D correlation efficiency. Addressing these limitations, we here describe a novel pipeline for volume-CLEM that provides high-precision (<100nm) registration between 3D fluorescence microscopy (FM) and 3D electron microscopy (EM) data sets with significantly increased throughput. Using multi-modal fiducial nanoparticles that remain fluorescent in epoxy resins and a 3D confocal fluorescence microscope integrated in a Focused Ion Beam Scanning Electron Microscope (FIB.SEM), our approach uses FM to target extremely small volumes of even single organelles for imaging in volume-EM, and obviates the need for post correlation of big 3D datasets. We extend our targeted volume-CLEM approach to include live-cell imaging, adding information on the motility of intracellular membranes selected for volume-CLEM. We demonstrate the power of our approach by targeted imaging of rare and transient contact sites between endoplasmic reticulum (ER) and lysosomes within hours rather than days. Our data suggest that extensive ER-lysosome and mitochondria-lysosome interactions restrict lysosome motility, highlighting the unique capabilities of our integrated CLEM pipeline for linking molecular dynamic data to high-resolution ultrastructural detail in 3D.

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SKIP ‐ HOPS recruits TBC 1D15 for a Rab7‐to‐Arl8b identity switch to control late endosome transport

Cited by 65 publications

References 92 publications

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

RUFY3 and RUFY4 are ARL8 effectors that couple lysosomes to dynein-dynactin

Correlative Organelle Microscopy: fluorescence guided volume electron microscopy of intracellular processes

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