Maturation of Autophagic Vacuoles in Mammalian Cells

Eskelinen, Eeva‐Liisa

doi:10.4161/auto.1.1.1270

Cited by 560 publications

(483 citation statements)

References 70 publications

(114 reference statements)

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“…We found cells with an endosomal-like pool of mTOR (top), others with a highly perinuclear-pattern (bottom left), as well as others with a cytosolic pool (bottom right). mTOR-positive membranes were found to colocalize with Rab7 (a small GTPase involved in lysosome biogenesis and maturation of late autophagic compartments 8,[11][12][13] (Fig. 1B).…”

Section: Introductionmentioning

confidence: 99%

“…In cells coexpressing fluorescently-tagged RIα and LC3 (mammalian homologue of yeast Atg8 that specifically associates with membranes of mature autophagosomes [7][8][9] ), almost all RIα molecules were found to reside on LC3-positive membranes. Furthermore, in prkar1a -/-mouse embryonic fibroblasts the number of autophagosomes was reduced compared to the wild-type cells.…”

Section: Introductionmentioning

confidence: 99%

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mTOR Kinase and the Regulatory Subunit of Protein Kinase A (PRKAR1A) Spatially and Functionally Interact during Autophagosome Maturation

Mavrakis¹,

Lippincott‐Schwartz²,

Stratakis³

et al. 2007

Autophagy

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mTOR Kinase and the Regulatory Subunit of Protein Kinase A (PRKAR1A) Spatially and Functionally Interact during Autophagosome Maturation

Mavrakis¹,

Lippincott‐Schwartz²,

Stratakis³

et al. 2007

Autophagy

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“…These fusion events indicate that maturation of autophagosome to autophagolysosome, in mammalian cells, is a multistep process. 17 This convergence between the endocytic and autophagic pathways has been reported in Leydig cells. In this study, the authors have visualized by electron microscopy that MVBs deliver their endocytosed markers (two type of lectins, concanavalin A (ConA) and wheat germ agglutinin (WGA)) to the early autophagosomes where the two pathways meet.…”

mentioning

confidence: 99%

Autophagy and multivesicular bodies: two closely related partners

2008

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In the majority of cell types, multivesicular bodies (MVBs) are a special kind of late endosomes, crucial intermediates in the internalization of nutrients, ligands and receptors through the endolysosomal system. ESCRT-0, I, II and III (endosomal sorting complex required for transport) are involved in the sorting of proteins into MVBs, generating the intraluminal vesicles. Autophagy is a lysosomal degradation pathway for cytoplasmic components such as proteins and organelles. The autophagosome, a well-characterized structure of the autophagy pathway, can fuse with endocytic structures such as MVBs to generate the amphisome. Finally, the amphisome fuses with the lysosome to degrade the material wrapped inside. Currently, clear evidence suggests that efficient autophagic degradation requires functional MVBs. This review highlights the most recent advances in our understanding of the molecular machinery that participates in MVB biogenesis and regulates the interplay between autophagy and this organelle.

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“…Regulated autophagy can promote cell survival by providing metabolic fuel for mitochondrial oxidation after lysosomal digestion of intracellular components (Eskelinen, 2005;Lum et al, 2005b). Indeed, cells incapable of apoptosis can survive for an extended time after growth factor withdrawal or nutrient deprivation by utilizing autophagy as a source of nutrients to support basal cell metabolism (Lum et al, 2005a;Degenhardt et al, 2006;Fung et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

Altman¹,

Wofford²,

Zhao³

et al. 2009

MBoC

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Tissue homeostasis is controlled by the availability of growth factors, which sustain exogenous nutrient uptake and prevent apoptosis. Although autophagy can provide an alternate intracellular nutrient source to support essential basal metabolism of apoptosis-resistant growth factor-withdrawn cells, antiapoptotic Bcl-2 family proteins can suppress autophagy in some settings. Thus, the role of autophagy and interactions between autophagy and apoptosis in growth factor-withdrawn cells expressing Bcl-2 or Bcl-xL were unclear. Here we show autophagy was rapidly induced in hematopoietic cells upon growth factor withdrawal regardless of Bcl-2 or Bcl-xL expression and led to increased mitochondrial lipid oxidation. Deficiency in autophagy-essential gene expression, however, did not lead to metabolic catastrophe and rapid death of growth factor-deprived cells. Rather, inhibition of autophagy enhanced survival of cells with moderate Bcl-2 expression for greater than 1 wk, indicating that autophagy promoted cell death in this time frame. Cell death was not autophagic, but apoptotic, and relied on Chop-dependent induction of the proapoptotic Bcl-2 family protein Bim. Therefore, although ultimately important, autophagy-derived nutrients appear initially nonessential after growth factor withdrawal. Instead, autophagy promotes tissue homeostasis by sensitizing cells to apoptosis to ensure only the most apoptosis-resistant cells survive long-term using autophagy-derived nutrients when growth factor deprived. INTRODUCTIONMetazoan cells require growth factor input to maintain metabolism and viability in both development and tissue homeostasis (Raff, 1992;Rathmell et al., 2000). The phosphoinositide 3-kinase (PI3K)-Akt mammalian target of rapamycin (mTOR) pathway is an important signaling mechanism of many growth factors that maintains nutrient uptake and prevents apoptotic cell death (Vivanco and Sawyers, 2002;Wieman et al., 2007). When cells are deprived of appropriate growth factor stimulation, the loss of PI3K-AktmTOR signaling, glucose transporter localization on the cell surface, and glucose uptake leads to apoptosis or autophagy (Tsujimoto and Shimizu, 2005;Wieman et al., 2007). Unlike the cell death pathway of apoptosis, autophagy is a dualfunction mechanism of bulk cytoplasmic and organelle degradation in lysosomes that can promote cell survival if controlled or can lead to death if excessive. The regulation of autophagy and how it impacts apoptosis and cell fate upon growth factor withdrawal, however, remain uncertain.Autophagy may influence cell fate upon growth factor deprivation by multiple mechanisms. Regulated autophagy can promote cell survival by providing metabolic fuel for mitochondrial oxidation after lysosomal digestion of intracellular components (Eskelinen, 2005;Lum et al., 2005b). Indeed, cells incapable of apoptosis can survive for an extended time after growth factor withdrawal or nutrient deprivation by utilizing autophagy as a source of nutrients to support basal cell metabolism (Lum et al., 2005a;Dege...

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Maturation of Autophagic Vacuoles in Mammalian Cells

Cited by 560 publications

References 70 publications

mTOR Kinase and the Regulatory Subunit of Protein Kinase A (PRKAR1A) Spatially and Functionally Interact during Autophagosome Maturation

mTOR Kinase and the Regulatory Subunit of Protein Kinase A (PRKAR1A) Spatially and Functionally Interact during Autophagosome Maturation

Autophagy and multivesicular bodies: two closely related partners

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

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