GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion

Wang, Hanzhi; Sun, Huajun; Zhu, Xiaohui; Zhang, Li; Albanesi, Joseph P.; Levine, Beth; Yin, Helen L.

doi:10.1073/pnas.1507263112

Cited by 179 publications

(185 citation statements)

References 23 publications

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“…In contrast to dengue virus, the autophagic vacuole shows no evidence of being the site of replication for JEV. However, this finding is not consistent with the experiments conducted by Jin et al [48] and Wang et al [49] , who stated that the accumulation of the autophagosome and the autophagosome-lysosome fusion are essential to promote JEV replication [47][48][49] . In addition to initiating autophagy, viral intrusion also affects the intermediate step of the event.…”

Section: Autophagy Induction and Intracellular Replication In Viral Ccontrasting

confidence: 77%

Interactions between neurotropic pathogens, neuroinflammatory pathways, and autophagic neural cell death

Sahu¹,

Ter²

2018

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In recent times, there has been a significant increase in studies focusing on immunological functions of autophagy, however, knowledge of its roles and regulations in the central nervous system remains unclear. Present reviews highlight the molecular cross talk between host cell autophagy with inflammatory pathways in the context of neuro-infections. Intracellular pathogens might have an ability to manipulate the autophagy regulation process. An augmented autophagy and inflammation at the site of infection is traditionally considered host protective. Moreover, host cell autophagy might also facilitate pathogen survivability and multiplication in the brain environment. Consequently, an excessive autophagy and neuroinflammatory process do put surrounding healthy brain tissue at risk of pathogen invasion. The question arises, whether there are any known direct interactions of intracellular neurotropic pathogens with this degradative pathway that favour intracerebral pathogen survival and growth? It is worth exploring any such cooperation between pathogen factors and altered immune pathways that modulate autophagy regulatory genes causing massive neuronal damage. A detailed understanding of molecular mechanisms in microbial pathogenesis, neuroinflammatory and neuronal autophagy pathways might identify novel therapeutic targets and diagnostic biomarkers.

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Section: Autophagy Induction and Intracellular Replication In Viral Ccontrasting

confidence: 77%

Interactions between neurotropic pathogens, neuroinflammatory pathways, and autophagic neural cell death

Sahu¹,

Ter²

2018

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“…Phosphatidylinositol 4-kinase type 2-alpha (PI4KIIα) normally localizes to the perinuclear region and the trans-Golgi network (TGN). Upon starvation, PI4KIIα exits the TGN and disperses into the cytoplasm, with some PI4KIIα localizing to autophagosomes in a palmitoylationdependent manner with a similar redistribution of PI4P (Wang et al, 2015). Consistent with this, depletion of PI4KIIα reduces the concentration of PI4P in autophagosomes.…”

Section: Phosphoinositides In Autophagosome-lysosome Fusionmentioning

confidence: 64%

“…Knockdown of either GABARAP or PI4KIIα creates defective, large autophagosomes and impairs the degradation of LC3 and p62, owing to defective autophagosomal fusion with the lysosome. Importantly, this fusion defect is rescued by introduction of PI4P, but not of phosphatidylinositol (4,5)-bisphosphate, suggesting that the generation of PI4P specifically -and not its downstream metabolites -is essential for autophagosome-lysosome fusion (Wang et al, 2015). However, the exact role of PI4P in the fusion process needs to be clarified in future studies.…”

Section: Phosphoinositides In Autophagosome-lysosome Fusionmentioning

confidence: 97%

“…Interestingly, PI4KIIα interacts with the Atg8 homologs GABARAP and GABARAPL2, but not with LC3. Depletion of GABARAP inhibits translocation of PI4KIIα to autophagosomes, whereas depletion of PI4KIIα does not affect GABARAP distribution, indicating that GABARAP functions upstream of PI4KIIα in this context (Wang et al, 2015). Knockdown of either GABARAP or PI4KIIα creates defective, large autophagosomes and impairs the degradation of LC3 and p62, owing to defective autophagosomal fusion with the lysosome.…”

Section: Phosphoinositides In Autophagosome-lysosome Fusionmentioning

confidence: 98%

“…The generation of PI4P [ phosphatidylinositol (4)-phosphate] on autophagosomes is crucial for autophagosome-lysosome fusion in mammals (Wang et al, 2015) (Fig. 4).…”

Section: Phosphoinositides In Autophagosome-lysosome Fusionmentioning

confidence: 99%

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New insights into autophagosome–lysosome fusion

Nakamura

Yoshimori

2017

Journal of Cell Science

446

324

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Macroautophagy (autophagy) is a highly conserved intracellular degradation system that is essential for homeostasis in eukaryotic cells. Due to the wide variety of the cytoplasmic targets of autophagy, its dysregulation is associated with many diseases in humans, such as neurodegenerative diseases, heart disease and cancer. During autophagy, cytoplasmic materials are sequestered by the autophagosome -a double-membraned structure -and transported to the lysosome for digestion. The specific stages of autophagy are induction, formation of the isolation membrane (phagophore), formation and maturation of the autophagosome and, finally, fusion with a late endosome or lysosome. Although there are significant insights into each of these steps, the mechanisms of autophagosomelysosome fusion are least understood, although there have been several recent advances. In this Commentary, we will summarize the current knowledge regarding autophagosome-lysosome fusion, focusing on mammals, and discuss the remaining questions and future directions of the field.

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Phosphoinositide‐binding proteins in autophagy

Lystad

Simonsen

2016

FEBS Letters

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Edited by Wilhelm JustPhosphoinositides represent a very small fraction of membrane phospholipids, having fast turnover rates and unique subcellular distributions, which make them perfect for initiating local temporal effects. Seven different phosphoinositide species are generated through reversible phosphorylation of the inositol ring of phosphatidylinositol (PtdIns). The negative charge generated by the phosphates provides specificity for interaction with various protein domains that commonly contain a cluster of basic residues. Examples of domains that bind phosphoinositides include PH domains, WD40 repeats, PX domains, and FYVE domains. Such domains often display specificity toward a certain species or subset of phosphoinositides. Here we will review the current literature of different phosphoinositide-binding proteins involved in autophagy.Keywords: autophagy; FYVE; PH; phosphoinositide; PX AutophagyAutophagy is the process by which cellular components are transported to the lysosome (or the yeast vacuole) for degradation to provide cellular homeostasis and quality control. There are three main forms of autophagy, namely microautophagy, which involves a direct engulfment of cytosolic cargo by the endosomal or lysosomal/vacuolar membrane, chaperone-mediated autophagy (CMA), involving lysosomal translocation of cytosolic protein cargo, and macroautophagy, a vesicle transport pathway where cargo is sequestered into double-membrane autophagosomes which undergo fusion with endosomes and/or the lysosome/vacuole. Autophagy is induced upon cellular stress (e.g., starvation) to facilitate cell survival by providing building blocks that can be used to produce essential molecules and generate energy. However, autophagy also serves an important quality control function under basal conditions by selective clearance of damaged or dysfunctional cellular components [1].Macroautophagy (hereafter autophagy) involves nucleation of a phagophore membrane (also called the isolation membrane) from specific phosphatidyl inositol 3-phosphate (PtdIns3P)-enriched structures, called the phagophore assembly site (PAS, a peri-vacuolar structure) in yeast and the omegasome (associated with the endoplasmic reticulum, ER) in mammals. Typically, there is only a single PAS in yeast, while several ER-associated omegasomes are detected upon Abbreviations ALFY, autophagy-linked FYVE protein; Arf6, adenosine diphosphate ribosylation factor 6; ATG, autophagy-related; BATS, biotin and thiamin synthesis-associated domain; Cvt, cytoplasm-to-vacuole; DFCP1, double FYVE-containing protein 1; ER, endoplasmic reticulum; FYCO1, FYVE and coiled-coil domain-containing 1; GRAM, glycosyltransferases Rab-like GTPase activators and myotubularins; HOPS, homotypic fusion and protein sorting; Hsv2, homologous with swollen vacuole phenotype 2; LIR, LC3-interacting region; MTMR3, myotubularin-related protein 3; mTORC1, mechanistic target of rapamycin complex 1; PA, phosphatidic acid; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide-dependent protein kinase ...

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GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion

Cited by 179 publications

References 23 publications

Interactions between neurotropic pathogens, neuroinflammatory pathways, and autophagic neural cell death

Interactions between neurotropic pathogens, neuroinflammatory pathways, and autophagic neural cell death

New insights into autophagosome–lysosome fusion

Phosphoinositide‐binding proteins in autophagy

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