Triggered recruitment of ESCRT machinery promotes endolysosomal repair

Skowyra, Michael L.; Schlesinger, Paul H.; Naismith, Teresa V.; Hanson, Phyllis I.

doi:10.1126/science.aar5078

Cited by 377 publications

(587 citation statements)

References 51 publications

(108 reference statements)

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“…Another possibility is that within live cells, EVs and their content are first partially digested in endosomes and then released within the cytosol by escaping from damaged endosomes [35]. Although we cannot rule out this possibility within intact cells, this seems unlikely because our in vitro assay does not deal with functional endo/lysosomes.…”

Section: Discussionmentioning

confidence: 96%

Content release of extracellular vesicles in a cell‐free extract

Bonsergent

Lavieu

2019

FEBS Letters

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Extracellular vesicles (EVs) transfer molecules from donor to acceptor cells. The EV‐content delivery process within the acceptor cell is poorly characterized. We developed a new cell‐free assay to assess EV‐content release in vitro. We found that EV‐cytosolic cargoes are released from EVs when isolated vesicles are incubated with purified plasma membrane sheets at acidic pH, a characteristic of the endolysosomal environment. This process is protein dependent. Our results suggest that EV‐content delivery occurs within the endo/lysosomes of acceptor cells and is triggered by acidification. This process resembles virus content delivery and may require membrane fusion. The assay presented here will facilitate investigations into the core machinery and mechanisms underlying EV content delivery.

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Section: Discussionmentioning

confidence: 96%

Content release of extracellular vesicles in a cell‐free extract

Bonsergent

Lavieu

2019

FEBS Letters

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“…The immunoelectron microscopic analysis of BMDCs, as well as the disappearance over time of proteasome-containing puncta in BMDCs expressing the Rab mutants, suggests that entry of small vesicles containing proteasomes that are derived from the cytosol may be involved. The ESCRT components have been identified as key proteins that drive intraluminal vesicle budding but they also play a role in endolysosomal membrane repair (Skowyra et al, 2018), which also could potentially impact crosspresentation. The more notable ones are macroautophagy, chaperone-mediated autophagy, and budding of intraluminal vesicles (Crotzer & Blum, 2008).…”

Section: Discussionmentioning

confidence: 99%

Proteasomal degradation within endocytic organelles mediates antigen cross‐presentation

et al. 2019

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During MHC‐I‐restricted antigen processing, peptides generated by cytosolic proteasomes are translocated by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum, where they bind to newly synthesized MHC‐I molecules. Dendritic cells and other cell types can also generate MHC‐I complexes with peptides derived from internalized proteins, a process called cross‐presentation. Here, we show that active proteasomes within cross‐presenting cell phagosomes can generate these peptides. Active proteasomes are detectable within endocytic compartments in mouse bone marrow‐derived dendritic cells. In TAP‐deficient mouse dendritic cells, cross‐presentation is enhanced by the introduction of human β2‐microglobulin, which increases surface expression of MHC‐I and suggests a role for recycling MHC‐I molecules. In addition, surface MHC‐I can be reduced by proteasome inhibition and stabilized by MHC‐I‐restricted peptides. This is consistent with constitutive proteasome‐dependent but TAP‐independent peptide loading in the endocytic pathway. Rab‐GTPase mutants that restrain phagosome maturation increase proteasome recruitment and enhance TAP‐independent cross‐presentation. Thus, phagosomal/endosomal binding of peptides locally generated by proteasomes allows cross‐presentation to generate MHC‐I‐peptide complexes identical to those produced by conventional antigen processing.

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“…The ESCRT machinery can also seal membrane fenestrations at several sites, including the nuclear envelope (Denais et al 2016, Olmos et al 2015, Raab et al 2016, Vietri et al 2015), the plasma membrane (Jimenez et al 2014, Scheffer et al 2014), and endolysosomes (Skowyra et al 2018). The nuclear membrane has two opposed bilayers, and holes that cross both membranes are therefore filled with cytoplasm and are topologically equivalent to ILV bud necks.…”

Section: The Escrt Pathwaymentioning

confidence: 99%

Structures, Functions, and Dynamics of ESCRT-III/Vps4 Membrane Remodeling and Fission Complexes

McCullough

Frost

Sundquist

2018

Annu. Rev. Cell Dev. Biol.

229

272

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The endosomal sorting complexes required for transport (ESCRT) pathway mediates cellular membrane remodeling and fission reactions. The pathway comprises five core complexes: ALIX, ESCRT-I, ESCRT-II, ESCRT-III, and Vps4. These soluble complexes are typically recruited to target membranes by site-specific adaptors that bind one or both of the early-acting ESCRT factors: ALIX and ESCRT-I/ESCRT-II. These factors, in turn, nucleate assembly of ESCRT-III subunits into membrane-bound filaments that recruit the AAA ATPase Vps4. Together, ESCRT-III filaments and Vps4 remodel and sever membranes. Here, we review recent advances in our understanding of the structures, activities, and mechanisms of the ESCRT-III and Vps4 machinery, including the first high-resolution structures of ESCRT-III filaments, the assembled Vps4 enzyme in complex with an ESCRT-III substrate, the discovery that ESCRT-III/Vps4 complexes can promote both inside-out and outside-in membrane fission reactions, and emerging mechanistic models for ESCRT-mediated membrane fission.

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Triggered recruitment of ESCRT machinery promotes endolysosomal repair

Cited by 377 publications

References 51 publications

Content release of extracellular vesicles in a cell‐free extract

Content release of extracellular vesicles in a cell‐free extract

Proteasomal degradation within endocytic organelles mediates antigen cross‐presentation

Structures, Functions, and Dynamics of ESCRT-III/Vps4 Membrane Remodeling and Fission Complexes

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