The Autophagic and Endocytic Pathways Converge at the Nascent Autophagic Vacuoles

Liou, Willisa; Geuze, Hans J.; Geelen, M.J.H.; Slot, Jan W.

doi:10.1083/jcb.136.1.61

Cited by 256 publications

(220 citation statements)

References 22 publications

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“…The observation that lipid modulation at the plasma membrane has an impact on autophago-lysosomal accumulation argues in favor of two long debated issues in the autophagy field. They support the convergence of autophagy and endocytic pathways 41,42 and the contribution of the plasma membrane to the formation of the autophagosome membrane. 27,43,44 We believe these findings open interesting perspectives for NPA treatments aimed at avoiding SM accumulation at the plasma membrane, which could be a more accessible target than lysosomes.…”

Section: Discussionsupporting

confidence: 52%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions.

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Section: Discussionsupporting

confidence: 52%

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

et al. 2014

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“…Others believed that the convergence might be a multistage event [14][15][16]. In the present study, the endocytic and autophagic compartments can be readily identified in Leydig cells, which makes easier to define the stages of two pathways than was possible before.…”

Section: The Convergent Point Of Endocytic and Autophagic Pathwaysmentioning

confidence: 69%

The convergent point of the endocytic and autophagic pathways in leydig cells

Tang

1999

Cell Res

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Endocytic tracers and marker enzyme of lysosomes were used in the present study to analyze the processes of autophagocytosis and endocytosis, and the convergent point of these two pathways in Leydig cells. The endocytic and autophagic compartments can be easily identified in Leydig cells, which makes easier to define the stages of two pathways than was possible before. The evidences indicated that the late endosomes (dense MVBs) deliver their endocytosed gold tracers together with lysosomal enzymes to the early autophagosomes and they are the convergent point of the two pathways. During this convergent process, the early autophagosomes transform into late autophagosomes and the late endosomes transform into mature lysosomes.

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“…The appearance of heterologous transforming vacuoles after leupeptin treatment suggests that MLBs are continually fusing with lysosomes and that transformation of newly incorporated material into membrane lamellae requires lysosomal degradation. The endocytic pathway has been shown to deliver material to nascent autophagic vacuoles, and the autophagic pathway is therefore accessible at early stages (Gordon and Seglen, 1988;Tooze et al, 1990;Liou et al, 1997). Fusion of lysosomes with degradative autophagic vacuoles has also been documented (Ericsson, 1969;Lawrence and Brown, 1992;Yokota et al, 1995).…”

Section: Role Of Lysosomal Degradation In Mlb Biogenesismentioning

confidence: 99%

Biogenesis of Multilamellar Bodies via Autophagy

Hariri

Millane

Guimond

et al. 2000

MBoC

164

142

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Transfection of Mv1Lu mink lung type II alveolar cells with ␤1-6-N-acetylglucosaminyl transferase V is associated with the expression of large lysosomal vacuoles, which are immunofluorescently labeled for the lysosomal glycoprotein lysosomal-associated membrane protein-2 and the ␤1-6-branched N-glycan-specific lectin phaseolis vulgaris leucoagglutinin. By electron microscopy, the vacuoles present the morphology of multilamellar bodies (MLBs). Treatment of the cells with the lysosomal protease inhibitor leupeptin results in the progressive transformation of the MLBs into electron-dense autophagic vacuoles and eventual disappearance of MLBs after 4 d of treatment. Heterologous structures containing both membrane lamellae and peripheral electron-dense regions appear 15 h after leupeptin addition and are indicative of ongoing lysosome-MLB fusion. Leupeptin washout is associated with the formation after 24 and 48 h of single or multiple foci of lamellae within the autophagic vacuoles, which give rise to MLBs after 72 h. Treatment with 3-methyladenine, an inhibitor of autophagic sequestration, results in the significantly reduced expression of multilamellar bodies and the accumulation of inclusion bodies resembling nascent or immature autophagic vacuoles. Scrape-loaded cytoplasmic FITC-dextran is incorporated into lysosomal-associated membrane protein-2-positive MLBs, and this process is inhibited by 3-methyladenine, demonstrating that active autophagy is involved in MLB formation. Our results indicate that selective resistance to lysosomal degradation within the autophagic vacuole results in the formation of a microenvironment propicious for the formation of membrane lamella. INTRODUCTIONMultilamellar bodies (MLBs) are membrane-bound cellular organelles, which vary in size from 100-2400 nm, are composed of concentric membrane layers, and frequently exhibit an electron-dense core. MLBs are found in numerous cell types where they function in lipid storage and secretion (Schmitz and Mü ller, 1991). In lung type II alveolar cells, MLBs function as secretory granules whose exocytosis results in the deposition of the tubular myelin forms of surfactant on the surface of the alveolae (Hatasa and Nakamura, 1965;Ryan et al., 1975;Williams, 1977). The surfactant film over the alveolar epithelium regulates the surface tension at the air-cell interface and protects the alveola from collapse during respiration (Haagman and van Golde, 1991).Although the secretory function of MLBs in type II alveolar cells is well established, the precise mechanism of MLB biogenesis remains unclear. Autoradiographic studies of murine type II alveolar cells of mouse lungs showed that although phospholipids labeled with [ 3 H]choline are delivered directly from the Golgi to the MLB, proteins metabolically labeled with [ 3 H]leucine are visualized within multivesicular bodies before delivery to MLBs (Chevalier and Collet, 1972). Surfactant proteins A, B, and C are delivered via multivesicular bodies to MLBs, and multivesicular bodies are proposed as th...

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The Autophagic and Endocytic Pathways Converge at the Nascent Autophagic Vacuoles

Cited by 256 publications

References 22 publications

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A

The convergent point of the endocytic and autophagic pathways in leydig cells

Biogenesis of Multilamellar Bodies via Autophagy

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