Structural biology of the core autophagy machinery

Suzuki, Hisao; Osawa, Takuo; Fujioka, Yūko; Noda, Nobuo N.

doi:10.1016/j.sbi.2016.09.010

Cited by 116 publications

(98 citation statements)

References 62 publications

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“…Also, it can be activated through IRE1-JNK pathway [45]. Activation of IRE1 stimulates disruption of Beclin-1 inhibitory complexes through phosphorylation of Bcl-2, thereby triggering autophagy [46]. And the results in this study revealed both inhaling H2 and ischemic postconditioning could reduce the expressions of Bclin-1 and –Bcl-2/ Bcl-2 induced by I/R injury, besides, inhaling H 2 had a better effect in reducing the expression of these proteins when compared with ischemic postconditioning.…”

Section: Discussionmentioning

confidence: 99%

Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy

Gao

Yang

Chi

et al. 2017

Cell Physiol Biochem

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Background/Aims: To study the effect of inhaling hydrogen gas on myocardial ischemic/reperfusion(I/R) injury in rats. Methods: Seventy male Wistar albino rats were divided into five groups at random as the sham group (Sham). The I/R group (I/R), The ischemic postconditioning group (IPo), The I/R plus hydrogen group (IH₂) and the ischemic postconditioning plus hydrogen group (IPoH₂). The Sham group was without coronary occlusion. In I/R group, Ischemic/reperfusion injury was induced by coronary occlusion for 1 hour. Followed by 2 hours of reperfusion. In the IPo and IPoH2 group, four cycles of 1 min reperfusion/1 min ischemia was given at the end of 1 hour coronary occlusion. While 2% hydrogen was administered by inhalation 5 min before reperfusion till 2 hours after reperfusion in both the IPoH2 and IH2 group. The heart and blood samples were harvested at the end of the surgical protocol. Then the myocardium cell endoplasmic reticulum(ER) stress and autophagy was observed by electron microscope. In addition, the cardiac ER stress and autophagy related proteins expression were detected by Western blotting analysis. Results: Both inhaling 2% hydrogen and ischemic postconditioning treatment reduced the ischemic size and serum troponin I level in rats with I/R injury, and inhaling hydrogen showed a more curative effect compared with ischemic postconditioning treatment. Meanwhile inhaling hydrogen showed a better protective effect in attenuating tissue reactive oxygen species. Malondialdehyde levels and immunoreactivities against 8-hydroxy-2’-deoxyguanosine and inhibiting cardiac endoplasmic reticulum stress and down-regulating autophagy as compared with ischemic postconditioning treatment. Conclusion: These results revealed a better protective effect of hydrogen on myocardial ischemic/reperfusion injury in rats by attenuating endoplasmic reticulum stress and down-regulating autophagy compared with ischemic postconditioning treatment.

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Section: Discussionmentioning

confidence: 99%

Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy

Gao

Yang

Chi

et al. 2017

Cell Physiol Biochem

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“…Subsequently, the beclin-1/vacuolar protein sorting 34 (BECN-1/Vps34) complex is recruited to catalyze the formation of phosphatidyl-inositol-3-phosphate (PI3P) [9], necessary for the formation of the preautophagosomal membrane or phagophore. The elongation of this structure is regulated by the sequential and coordinated action of autophagy-related (ATGs) proteins, leading to the formation of the autophagosome [9,10], the double-membrane bound vesicle that sequesters autophagic cargo on its lumen. Hence, ATG-3, ATG-4, and ATG-7 catalyze the lipidation of microtubule-associated light chain 3 (LC3), which accumulates in autophagosomal membranes and mediates cargo engulfment by binding to autophagic substrates.…”

Section: Autophagy: the Factsmentioning

confidence: 99%

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Plaza-Zabala

Sierra-Torre

Sierra

2017

IJMS

272

210

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Abstract:Autophagy is emerging as a core regulator of Central Nervous System (CNS) aging and neurodegeneration. In the brain, it has mostly been studied in neurons, where the delivery of toxic molecules and organelles to the lysosome by autophagy is crucial for neuronal health and survival. However, we propose that the (dys)regulation of autophagy in microglia also affects innate immune functions such as phagocytosis and inflammation, which in turn contribute to the pathophysiology of aging and neurodegenerative diseases. Herein, we first describe the basic concepts of autophagy and its regulation, discuss key aspects for its accurate monitoring at the experimental level, and summarize the evidence linking autophagy impairment to CNS senescence and disease. We focus on acute, chronic, and autoimmunity-mediated neurodegeneration, including ischemia/stroke, Alzheimer's, Parkinson's, and Huntington's diseases, and multiple sclerosis. Next, we describe the actual and potential impact of autophagy on microglial phagocytic and inflammatory function. Thus, we provide evidence of how autophagy may affect microglial phagocytosis of apoptotic cells, amyloid-β, synaptic material, and myelin debris, and regulate the progression of age-associated neurodegenerative diseases. We also discuss data linking autophagy to the regulation of the microglial inflammatory phenotype, which is known to contribute to age-related brain dysfunction. Overall, we update the current knowledge of autophagy and microglia, and highlight as yet unexplored mechanisms whereby autophagy in microglia may contribute to CNS disease and senescence.

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“…Autophagy is mainly regulated by a step-wise process including the formation of autophagosome (a double-membrane organelle), docking and fusion of autophagosome with lysosome/vacuole and proteases-mediated degradation of the cargos (27). A set of autophagy-related (ATG) proteins have been reported to function in different stages of autophagy (27,28). To test whether autophagy pathway regulates Rph1 degradation upon DNA damage stress, cells were treated with a protease inhibitor, Phenylmethanesulfonyl fluoride (PMSF), to block vacuolar proteolysis.…”

Section: Resultsmentioning

confidence: 99%

Gcn5-mediated Rph1 acetylation regulates its autophagic degradation under DNA damage stress

Zheng

Chen

et al. 2017

Nucleic Acids Research

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Histone modifiers regulate proper cellular activities in response to various environmental stress by modulating gene expression. In budding yeast, Rph1 transcriptionally represses many DNA damage or autophagy-related gene expression. However, little is known how Rph1 is regulated during these stress conditions. Here, we report that Rph1 is degraded upon DNA damage stress conditions. Notably, this degradation occurs via the autophagy pathway rather than through 26S proteasome proteolysis. Deletion of ATG genes or inhibition of vacuole protease activity compromises Rph1 turnover. We also determine that Rph1 and nuclear export protein Crm1 interact, which is required for Rph1 translocation from the nucleus to the cytoplasm. More importantly, Gcn5 directly acetylates Rph1 in vitro and in vivo, and Gcn5-containing complex, SAGA, is required for autophagic degradation of Rph1. Gcn5-mediated Rph1 acetylation is essential for the association of Rph1 with the nuclear pore protein Nup1. Finally, we show that sustaining high levels of Rph1 during DNA damage stress results in cell growth defects. Thus, we propose that Gcn5-mediated acetylation finely regulates Rph1 protein level and that autophagic degradation of Rph1 is important for cell homeostasis. Our findings may provide a general connection between DNA damage, protein acetylation and autophagy.

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Structural biology of the core autophagy machinery

Cited by 116 publications

References 62 publications

Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy

Hydrogen Gas Attenuates Myocardial Ischemia Reperfusion Injury Independent of Postconditioning in Rats by Attenuating Endoplasmic Reticulum Stress-Induced Autophagy

Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging

Gcn5-mediated Rph1 acetylation regulates its autophagic degradation under DNA damage stress

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