Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy

Kobayashi, Satoru

doi:10.1248/bpb.b15-00096

Cited by 115 publications

(91 citation statements)

References 61 publications

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“…It was hypothesized that a slight vacuolation may be present in the normal human placenta as a natural and physiological form of cell degradation which promotes survival. [20,21] Meng et al [2] found much more trophoblastic vacuoles in placentas of GDM compared to controls. [2] Hyperglycemia and hypoxia which have a role in the etiology of GDM may enhance the lysosome/vacuole functions of the trophoblasts, which result in widespread cytoplasmic vacuolation and altered transplacental metabolic exchange that may lead to cell death.…”

Section: Discussionmentioning

confidence: 98%

Ultrastructure of the placenta in gestational diabetes mellitus

Hassan¹,

Essa²

2016

Anatomy

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Objectives: The placenta plays critical roles during pregnancy and is essential for fetal growth and development. Its functions are determined by the ultrastructure of the placental barrier that is an important feature to maintain the exchange surface area between the fetus and the mother. Gestational diabetes mellitus (GDM) comprises unfit conditions for embryonic and feto-placental development, and may result in placental abnormalities. The aim of this study was to detect the ultrastructural changes of the placenta in women with GDM. Methods:The placentas of 10 women with GDM without pregestational diabetics, hypertension and chronic diseases and 10 controls were studied. Six control women were delivered vaginally and the remaining cases by caesarian section at a gestational age of 36 to 39 weeks. Placental samples were measured for their thickness and prepared for light and transmission electron microscopy study.Results: Light microscopic study of the control placentas showed numerous densely packed microvilli with syncytial knots and thin-walled blood vessels and wide intervillous spaces. The placentas of GDM cases showed reduced number of microvilli with syncytial knots, thick-walled vessels, edematous spaces, areas of fibrosis and perivillous fibrinoid degeneration. Electron microscopic study of the placentas of the control women showed terminal villi with a thick layer of syncytiotrophoblasts (Sy) with a lot of regular cylindrical microvilli and a thin layer of cytotrophoblasts (Cy). There were some endoplasmic reticulum cisternae besides few mitochondria. The underlying villus core was harboring fetal capillaries lined with flat endothelial cells and thin basement membrane. There was no fibrosis or edema. In the placenta of GDM women, there was hypertrophy of Cy with atrophy of Sy with multiple vacuoles and areas for glycogen storage. The subtrophoblastic membrane was thick and the microvilli were scarce. The villous core showed congested capillaries, stromal macrophages, edematous spaces, glycogen storage areas and fibrosis. Conclusion:All the changes in placentas of gestational diabetes were attributed to associated hypoxia and oxidative stress due to decreased uteroplacental flow that was aggravated by the thick placental barrier and the presence of edema, fibrosis and glycogen storage areas that increased the distance of transfer between the fetus and mother.

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Section: Discussionmentioning

confidence: 98%

Ultrastructure of the placenta in gestational diabetes mellitus

Hassan¹,

Essa²

2016

Anatomy

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“…Model building was performed with the cocrystal structure of human ATG4B with LC3 (1−120) as template (PDB code: 2Z0D) 12 using the following procedure: (1) in silico mutation of the TFG residues of LC3 into Z-FA(G)-FMK; (2) rebuilding of A280H using the structure 2Z0E 12 to reproduce the human sequence; (3) removal of the fluorine atom of Z-FA(G)-FMK and formation of a covalent bond between the sulfur atom of Cys74 and the reactive methylene unit of FMK. Here, the second, alternate conformation of the side chain of Cys74 in the crystal structure 2Z0D was used as this is closer to the FMK group.…”

Section: ■ Experimental Methodsmentioning

confidence: 99%

“…1 The hallmark of autophagy is the formation of autophagosomes and subsequent fusion with lysosomes to achieve degradation of their contents. Dysregulation of autophagy has been recently described in the pathogenesis of a variety of diseases such as cancer, neurodegenerative and metabolic disorders, and viral infections.…”

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confidence: 99%

Discovery of Fluoromethylketone-Based Peptidomimetics as Covalent ATG4B (Autophagin-1) Inhibitors

Qiu

Kuhn

Aebi

et al. 2016

ACS Med. Chem. Lett.

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ATG4B or autophagin-1 is a cysteine protease that cleaves ATG8 family proteins. ATG4B plays essential roles in the autophagosome formation and the autophagy pathway. Herein we disclose the design and structural modifications of a series of fluoromethylketone (FMK)-based peptidomimetics as highly potent ATG4B inhibitors. Their structure−activity relationship (SAR) and protease selectivity are also discussed.KEYWORDS: ATG4B, autophagy, covalent inhibitor, fluoromethylketone, peptidomimetics A utophagy is an evolutionarily conserved process essential for cell homeostasis and housekeeping by catabolizing aggregated proteins and damaged cellular components. 1 The hallmark of autophagy is the formation of autophagosomes and subsequent fusion with lysosomes to achieve degradation of their contents. Dysregulation of autophagy has been recently described in the pathogenesis of a variety of diseases such as cancer, neurodegenerative and metabolic disorders, and viral infections. 2,3 Modulation of autophagy has become a very active area of preclinical and clinical research, and particularly, there is high interest to identify potent and specific autophagy inhibitors. 4 ATG4 or autophagins are a class of cytosolic cysteine proteases that cleave ATG8 family proteins, such as light chain 3 (LC3). ATG4 plays essential roles in the formation and maturation of autophagosomes. 5,6 Among all four human ATG4 orthologues, ATG4B is functionally dominant, and it is the sole enzyme reported to efficiently cleave LC3 precursors and to deconjugate lipid from membrane bound LC3-phosphatidylethanolamine (LC3-PE). 7 ATG4B has been considered as a potential therapeutic target in the development of chemosensitizer for the treatment of certain cancer types. Recently, a number of small molecule ATG4B inhibitors such as Z-L-Phe-chloromethylketone and NSC185058 were reported to have modulatory effects on the autophagy process. 8−10 However, because of its high chemical reactivity, the chloromethylketone moiety is usually associated with significant cytotoxicity. NSC185058, however, is only a weak ATG4B inhibitor with an IC 50 of 51 μM in an assay detecting the cleavage of LC3-GST. 10 Previously, we reported the identification of Z-FA-FMK (1, Figure 1) as a covalent active-site directed ATG4B inhibitor from a TR-FRET based focused library screening. 11 The hit expansion of 1 led to the discovery of Z-FG-FMK (2), which was 10-times more potent than 1 with an IC 50 of 1.2 μM in the biochemical assay. 11 Herein we disclose the structure-guided optimization of 2 toward highly potent fluoromethylketone (FMK)-based ATG4B inhibitors.As an early step in the autophagosome formation, ATG4B cleaves proLC3 to expose the C-terminal Gly120 for subsequent PE-conjugation and autophagosome membrane insertion. 5 The cocrystal structures of catalytically inert C74S or

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“…Autophagy, also called self-eating, a natural and evolutionarily conserved lysosomal degradation and renovation process to hydrolyze unused or dysfunctional cellular components, such as long-lived or misfold proteins and useless organelles [23]. Actually, the basal autophagy activity is essential for cell homeostasis, involving cell growth, survival, development and death.…”

Section: Autophagy: a Brief Introductionmentioning

confidence: 99%

“…One common hallmark of autophagy is mediated by the multiple autophagy-related (Atg) genes and their associated enzymes. The main and most common pathway, macroautophagy, usually called autophagy, is an intracellular recycling system, used primarily to mediate bulk degradation of superfluous or damaged cytosolic materials [23]. This autophagy processes include several In the breakdown step, autophagic materials or contents are hydrolyzed by lysosomal enzymes in autolysosome.…”

Section: Autophagy: a Brief Introductionmentioning

confidence: 99%

Dual Roles of CD38 in Autophagy

Wang¹,

Song²,

Wu³

et al. 2017

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CD38 is a versatile, ubiquitously expressed protein that was identified as a multifunctional enzyme. Recently, cumulating evidence has suggested that CD38 is involved in autophagy, which is an evolutionarily conserved lysosomal degradation and recycling system. Acting as a enzyme, CD38 utilizes nicotinamide adenine dinucleotide phosphate (NADP) to synthesize nicotinic acid adenine dinucleotide phosphate (NAADP), which acts as a key messenger for Ca 2+ -mobilizing in lysosome by targeting two-pore channels (TPCs) or transient receptor potential mucolipins (TRPMLs). Multiple studies have indicated that CD38 is involved in autophagy by modulating intracellular Ca 2+ signaling. However, the control of autophagy by CD38 signaling is the subject of two contrary views. The autophagosomes trafficking and fusion with lysosomes to form autolysosomes are crucial steps in autophagy. On the one hand, the available evidence indicates that lysosome trafficking and fusion to autophagosomes is positively modulated by CD38. On the other hand, overexpression of TPC2, which is positively modulated by CD38, was shown to promote the accumulation of autophagosomes, thus suppress autophagy. This review will reveal the interesting contrary dual roles of CD38 in autophagy, and critical insight into the molecular mechanisms of CD38 in autophagy regulation.

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Choose Delicately and Reuse Adequately: The Newly Revealed Process of Autophagy

Cited by 115 publications

References 61 publications

Ultrastructure of the placenta in gestational diabetes mellitus

Ultrastructure of the placenta in gestational diabetes mellitus

Discovery of Fluoromethylketone-Based Peptidomimetics as Covalent ATG4B (Autophagin-1) Inhibitors

Dual Roles of CD38 in Autophagy

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