SNARE Proteins Are Required for Macroautophagy

Nair, Usha; Jotwani, Anjali; Geng, Jiefei; Gammoh, Noor; Richerson, Diana; Yen, Wei Lien; Griffith, Janice; Nag, Shanta; Wang, Ke; Moss, Tyler J.; Baba, Misuzu; McNew, James A.; Jiang, Xuejun; Reggiori, Fulvio; Melia, Thomas J.; Klionsky, Daniel J.

doi:10.1016/j.cell.2011.06.022

Cited by 405 publications

(404 citation statements)

References 56 publications

(58 reference statements)

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“…Long implicated in LD fusion, 12 SNAREs have recently been described to mediate autophagosome biogenesis. 13,14 Another possibility is LC3, which is a protein critical for autophagosome membrane formation. 7 The finding that LC3 associates with LDs in the apparent absence of an autophagosomal membrane 1,15 suggests that this protein may function in LD recognition.…”

Section: Intracellular Lipids Are Degraded By Lipophagymentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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Intracellular lipids are stored in lipid droplets (LDs) and metabolized by cytoplasmic neutral hydrolases to supply lipids for cell use. Recently, an alternative pathway of lipid metabolism through the lysosomal degradative pathway of autophagy has been described and termed lipophagy. In this form of lipid metabolism, LD triglycerides (TGs) and cholesterol are taken up by autophagosomes and delivered to lysosomes for degradation by acidic hydrolases. Free fatty acids generated by lipophagy from the breakdown of TGs fuel cellular rates of mitochondrial b-oxidation. Lipophagy therefore functions to regulate intracellular lipid stores, cellular levels of free lipids such as fatty acids and energy homeostasis. The amount of lipid metabolized by lipophagy varies in response to the extracellular supply of nutrients. The ability of the cell to alter the amount of lipid targeted for autophagic degradation depending on nutritional status demonstrates that this process is selective. Intracellular lipids themselves regulate levels of autophagy by unclear mechanisms. Impaired lipophagy can lead to excessive tissue lipid accumulation such as hepatic steatosis, alter hypothalamic neuropeptide release to affect body mass, block cellular transdifferentiation and sensitize cells to death stimuli. Future studies will likely identify additional mechanisms by which lipophagy regulates cellular physiology, making this pathway a potential therapeutic target in a variety of diseases. Open QuestionsHow does the autophagic machinery selectively target stored lipids for degradation in response to changes in nutrient levels? What are the relative contributions of cytosolic lipolysis and lipophagy to lipid metabolism in different cell types, and is there cross-talk between the two pathways? What are the mechanisms by which intracellular lipids and other factors regulate levels of lipophagy? Do defects in lipophagy underlie human disease and can lipophagy be a therapeutic target? Intracellular lipids are essential to cells as an energy source, structural components for membranes, synthetic building blocks for other molecules, such as hormones, and as mediators of cell signaling. The ability to safely store adequate, but not excessive, amounts of lipids and to metabolize them when needed is critical for cell function and survival. The recent finding that lipids can be selectively degraded by the lysosomal pathway of macroautophagy through a process termed lipophagy 1 has opened up a new understanding of how lipid metabolism regulates cellular physiology and pathophysiology. Many new functions for autophagic lipid metabolism have now been defined in diverse cellular processes ranging from transdifferentiation to resistance to death. Intracellular Lipids are Degraded by LipophagyTGs and cholesterol are safely stored as neutral lipids in specialized cellular organelles called LDs. 2,3 Until recently, the breakdown of LD-stored TG and cholesterol was attributed exclusively to the actions of cytosolic hydrolytic enzymes or lipases. The role of l...

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Section: Intracellular Lipids Are Degraded By Lipophagymentioning

confidence: 99%

Regulation of lipid stores and metabolism by lipophagy

2012

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“…The Atg9 vesicle fusion mechanism may involve the yeast Rab protein Ypt1 and its GEF complex (the TRAPP III complex), which are required for autophagy and were identified in purified Atg9 vesicles [90,91]. In addition, SNARE proteins required for autophagosome formation in yeast have also been implicated in Atg9 vesicle fusion [92].…”

Section: Atg9 Vesicles As a Membrane Sourcementioning

confidence: 99%

A current perspective of autophagosome biogenesis

2013

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Autophagy is a bulk degradation system induced by cellular stresses such as nutrient starvation. Its function relies on the formation of double-membrane vesicles called autophagosomes. Unlike other organelles that appear to stably exist in the cell, autophagosomes are formed on demand, and once their formation is initiated, it proceeds surprisingly rapidly. How and where this dynamic autophagosome formation takes place has been a long-standing question, but the discovery of Atg proteins in the 1990's significantly accelerated our understanding of autophagosome biogenesis. In this review, we will briefly introduce each Atg functional unit in relation to autophagosome biogenesis, and then discuss the origin of the autophagosomal membrane with an introduction to selected recent studies addressing this problem.

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“…What governs and coordinates insulin degradation? Recent reports showed that SNAP receptor (SNARE) proteins play an important role in the regulation of autophagy [73]. SNARE proteins are involved both in insulin granule exocytosis and autophagosome and/or lysosome trafficking.…”

Section: Autophagy In Beta Cell Physiology and Diabetesmentioning

confidence: 99%

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

et al. 2014

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Autophagy is a lysosomal degradation pathway recycling intracellular long-lived proteins and damaged organelles, thereby maintaining cellular homeostasis. In addition to inflammatory processes, autophagy has been implicated in the regulation of adipose tissue and beta cell functions. In obesity and type 2 diabetes autophagic activity is modulated in a tissue-dependent manner. In this review we discuss the regulation of autophagy in adipose tissue and beta cells, exemplifying tissue-specific dysregulation of autophagy and its implications for the pathophysiology of obesity and type 2 diabetes. We will highlight common themes and outstanding gaps in our understanding, which need to be addressed before autophagy could be envisioned as a therapeutic target for the treatment of obesity and diabetes.

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SNARE Proteins Are Required for Macroautophagy

Cited by 405 publications

References 56 publications

Regulation of lipid stores and metabolism by lipophagy

Regulation of lipid stores and metabolism by lipophagy

A current perspective of autophagosome biogenesis

Autophagy in adipose tissue and the beta cell: implications for obesity and diabetes

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