Autophagy and multivesicular bodies: two closely related partners

Fader, Claudio Marcelo; Colombo, María Isabel

doi:10.1038/cdd.2008.168

Cited by 387 publications

(340 citation statements)

References 99 publications

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“…As the small GTPase Rab11 is essential both for exocytic trafficking from REs and for amphisome formation by fusion of multivesicular bodies (MVBs) with autophagosomes, 36 we investigated trafficking organelles involved in the recycling and degradation pathways. In dendrites of neurons cotransfected with Rab11-EYFP, Rab11 distribution changed from diffuse dendritic staining in HttQ25-GFP-expressing neurons to punctuate clustering around protein aggregates in those expressing HttQ47-GFP (Figures 4a and b).…”

Section: Resultsmentioning

confidence: 99%

“…46 The MVB is a late endocytic trafficking vesicle containing a number of internal vesicles of low pH that facilitate proteolysis, which fuse with autophagosomes in a Rab11-dependent step to form a hybrid organelle; the amphisome. 36,38 In the final stage, amphisomes fuse with lysosomes to generate autolysosomes that degrade susceptible cargo.…”

Section: Discussionmentioning

confidence: 99%

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Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease

et al. 2010

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Huntington's disease (HD) is a fatal neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein (htt) that mediates formation of intracellular protein aggregates. In the brains of HD patients and HD transgenic mice, accumulation of protein aggregates has been causally linked to lesions in axo-dendritic and synaptic compartments. Here we show that dendritic spines -sites of synaptogenesis -are lost in the proximity of htt aggregates because of functional defects in local endosomal recycling mediated by the Rab11 protein. Impaired exit from recycling endosomes (RE) and association of endocytosed protein with intracellular structures containing htt aggregates was demonstrated in cultured hippocampal neurons cells expressing a mutant htt fragment. Dendrites in hippocampal neurons became dystrophic around enlarged amphisome-like structures positive for Rab11, LC3 and mutant htt aggregates. Furthermore, Rab11 overexpression rescues neurodegeneration and dramatically extends lifespan in a Drosophila model of HD. Our findings are consistent with the model that mutant htt aggregation increases local autophagic activity, thereby sequestering Rab11 and diverting spine-forming cargo from RE into enlarged amphisomes. This mechanism may contribute to the toxicity caused by protein misfolding found in a number of neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease

et al. 2010

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“…In this regard, it should be noted that classical morphological studies showed the existence of a hybrid organelle of autophagosomes and early/late endosomes, termed amphisomes. 45 The SNARE molecule involved in lysosomal fusion may be delivered through amphisome formation, but this would still leave the question of how the SNARE involved in amphisome fusion is delivered. To date, no specific v-SNARE has been assigned as such a candidate, and identification of the v-SNARE would give us a critical clue to the identity of the source of the autophagosome membrane.…”

Section: Transport and Fusionmentioning

confidence: 99%

The late stages of autophagy: how does the end begin?

2009

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Autophagy is a catabolic cellular process involving dynamic membrane rearrangement. Here, we review the understanding of autophagy, focusing on the late stages of the process, from the closing of the autophagosome to fusion with the lysosome. We propose the Reverse fusion model, for the closing autophagosome. In this model, autophagosome closure proceeds in a topologically similar but reverse order to membrane fusion during the escape of influenza virus from the endosome. This dynamic process is thought to be directly catalyzed by LC3, an ubiquitin-like molecule. Further, we discuss the dynamics of the Atg16L complex in relation to the LC3 localization in these processes. Finally, the molecular mechanisms involved in the delivery of autophagosomes to the lysosome and fusion are introduced. Several key events exist in each step and seem to be coordinated to faithfully conduct the autophagic process.

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“…Most interestingly, GBPs functionally cooperate with different members of the p47 GTPase family (60,61), which are thought to induce interaction of chlamydial structures with autophagosomes to reroute the pathogen to autolysosomes (62). For cargo degradation by cathepsins (63,64), autophagosomes fuse with endosomes to form multivesicular amphisomes (44). It was recently proposed that amphisomes are involved in pathogen degradation and Ag presentation in DCs (65).…”

Section: Discussionmentioning

confidence: 99%

“…Most interestingly, the vesicular compartments (Fig. 3C, indicated by orange color) surrounding the disintegrated inclusions (44).…”

Section: Cellular Characteristics Of Chlamydial Inclusions Within Infmentioning

confidence: 99%

Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

Fiegl

Kägebein

Liebler-Tenorio

et al. 2013

The Journal of Immunology

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Dendritic cells (DCs) are among the first professional APCs encountered by the obligate intracellular bacterium Chlamydia during infection. Using an established mouse bone marrow–derived DC line, we show that DCs control chlamydial infection in multiple small inclusions characterized by restricted bacterial growth, impaired cytosolic export of the virulence factor chlamydial protease–like activity factor, and interaction with guanylate-binding protein 1, a host cell factor involved in the initiation of autophagy. During maturation of infected DCs, chlamydial inclusions disintegrate, likely because they lack chlamydial protease–like activity factor–mediated protection. Released cytosolic Chlamydia are taken up by autophagosomes and colocalize with cathepsin-positive amphisomal vacuoles, to which peptide transporter TAP and upregulated MHC class I (MHC I) are recruited. Chlamydial Ags are subsequently generated through routes involving preprocessing in amphisomes via cathepsins and entry into the cytosol for further processing by the proteasome. Finally, bacterial peptides are reimported into the endosomal pathway for loading onto recycling MHC I. Thus, we unravel a novel pathway of MHC I–mediated cross-presentation that is initiated with a host cellular attack physically disrupting the parasitophorous vacuole, involves autophagy to collect cytosolic organisms into autophagosomes, and concludes with complex multistep antigenic processing in separate cellular compartments.

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Autophagy and multivesicular bodies: two closely related partners

Cited by 387 publications

References 99 publications

Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease

Dendritic spine loss and neurodegeneration is rescued by Rab11 in models of Huntington's disease

The late stages of autophagy: how does the end begin?

Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells

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