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Autophagy

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https://www.readbyqxmd.com/read/28820312/architecture-of-the-atg2b-wdr45-complex-and-an-aromatic-y-hf-motif-crucial-for-complex-formation
#1
Jing-Xiang Zheng, Yan Li, Yue-He Ding, Jun-Jie Liu, Mei-Jun Zhang, Meng-Qiu Dong, Hong-Wei Wang, Li Yu
PtdIns3P signaling is critical for dynamic membrane remodeling during autophagosome formation. Proteins in the Atg18/WIPI family are PtdIns3P-binding effectors which can form complexes with proteins in the Atg2 family, and both families are essential for macroautophagy/autophagy. However, little is known about the biophysical properties and biological functions of the Atg2-Atg18/WIPI complex as a whole. Here, we demonstrate that an ortholog of yeast Atg18, mammalian WDR45/WIPI4 has a stronger binding capacity for mammalian ATG2A or ATG2B than the other 3 WIPIs...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28820297/the-formation-of-autophagosomes-during-lysosomal-defect-a-new-source-of-cytotoxicity
#2
Robert W Button, Shouqing Luo
Macroautophagy/autophagy comprises autophagosome synthesis and lysosomal degradation. It is well known that lysosomal defects cause toxicity to cells. However, it has not been investigated previously if cytotoxicity is conferred by autophagosome formation during lysosomal defect. Recently, we found that the formation of autophagosomes in such conditions also causes cytotoxicity, in addition to lysosomal defect insults. We revealed that a partial reduction in autophagosome synthesis was beneficial for cell survival in cells bearing the autophagosome formation-based toxicity...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28820290/local-histone-acetylation-by-acss2-promotes-gene-transcription-for-lysosomal-biogenesis-and-autophagy
#3
Xinjian Li, Xu Qian, Zhimin Lu
Overcoming metabolic stress is a critical step in tumorigenesis. Acetyl coenzyme A (acetyl-CoA) converted from glucose or acetate is a substrate used for histone acetylation to regulate gene expression. However, how acetyl-CoA is produced under nutritional stress conditions is unclear. Herein we report that nutritional stress induces nuclear translocation of ACSS2 (acyl-CoA synthetase short-chain family member 2). This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28820289/recent-advances-in-quantitative-and-chemical-proteomics-for-autophagy-studies
#4
Yin-Kwan Wong, Jianbin Zhang, Zi-Chun Hua, Qingsong Lin, Han-Ming Shen, Jigang Wang
Macroautophagy/autophagy is an evolutionarily well-conserved cellular degradative process with important biological functions that is closely implicated in health and disease. In recent years, quantitative mass spectrometry-based proteomics and chemical proteomics have emerged as important tools for the study of autophagy, through large-scale unbiased analysis of the proteome or through highly specific and accurate analysis of individual proteins of interest. At present, a variety of approaches have been successfully applied, including (i) expression and interaction proteomics for the study of protein post-translational modifications, (ii) investigating spatio-temporal dynamics of protein synthesis and degradation, and (iii) direct determination of protein activity and profiling molecular targets in the autophagic process...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28820286/autophagy-monitoring-and-autophagy-deficient-mice
#5
Akiko Kuma, Masaaki Komatsu, Noboru Mizushima
Discovery of yeast autophagy-related (ATG) genes and subsequent identification of their homologs in other organisms have enabled researchers to investigate physiological functions of macroautophagy/autophagy using genetic techniques. Specific identification of autophagy-related structures is important to evaluate autophagic activity, and specific ablation of autophagy-related genes is a critical means to determine the requirements of autophagy. Here, we review currently available mouse models, particularly focusing on autophagy (and mitophagy) indicator models and systemic autophagy-related gene-knockout mouse models...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28820284/bnip3l-nix-mediated-mitophagy-protects-against-ischemic-brain-injury-independent-of-park2
#6
Yang Yuan, Yanrong Zheng, Xiangnan Zhang, Ying Chen, Xiaoli Wu, Jiaying Wu, Zhe Shen, Lei Jiang, Lu Wang, Wei Yang, Jianhong Luo, Zhenghong Qin, Weiwei Hu, Zhong Chen
Cerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared, thus attenuating brain injury, by mitophagy. Here, we identified the involvement of BNIP3L/NIX in cerebral ischemia-reperfusion (I-R)-induced mitophagy. Bnip3l knockout (bnip3l(-/-)) impaired mitophagy and aggravated cerebral I-R injury in mice, which can be rescued by BNIP3L overexpression. The rescuing effects of BNIP3L overexpression can be observed in park2(-/-) mice, which showed mitophagy deficiency after I-R...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28820283/n-3-pufas-induce-inflammatory-tolerance-by-formation-of-keap1-containing-sqstm1-p62-bodies-and-activation-of-nfe2l2
#7
Jennifer Mildenberger, Ida Johansson, Ismail Sergin, Eli Kjøbli, Jan Kristian Damås, Babak Razani, Trude Helen Flo, Geir Bjørkøy
Inflammation is crucial in the defense against infections but must be tightly controlled to limit detrimental hyperactivation. Our diet influences inflammatory processes and omega-3 polyunsaturated fatty acids (n-3 PUFAs) have known anti-inflammatory effects. The balance of pro- and anti-inflammatory processes is coordinated by macrophages and macroautophagy/autophagy has recently emerged as a cellular process that dampens inflammation. Here we report that the n-3 PUFA docosahexaenoic acid (DHA) transiently induces cytosolic speckles of the autophagic receptor SQSTM1/p62 (sequestosome 1) (described as SQSTM1/p62-bodies) in macrophages...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28820282/mir505-3p-regulates-axonal-development-via-inhibiting-the-autophagy-pathway-by-targeting-atg12
#8
Kan Yang, Bin Yu, Cheng Cheng, Tianlin Cheng, Bo Yuan, Kai Li, Junhua Xiao, Zilong Qiu, Yuxun Zhou
In addition to the canonical role in protein homeostasis, autophagy has recently been found to be involved in axonal dystrophy and neurodegeneration. Whether autophagy may also be involved in neural development remains largely unclear. Here we report that Mir505-3p is a crucial regulator for axonal elongation and branching in vitro and in vivo, through modulating autophagy in neurons. We identify that the key target gene of Mir505-3p in neurons is Atg12, encoding ATG12 (autophagy related 12) which is an essential component of the autophagy machinery during the initiation and expansion steps of autophagosome formation...
August 18, 2017: Autophagy
https://www.readbyqxmd.com/read/28816597/the-ulk-complex-initiates-autophagosome-formation-at-phosphatidylinositol-synthase-enriched-er-subdomains
#9
Taki Nishimura, Noboru Mizushima
In our recent paper, we biochemically analyzed autophagosome-related membranes at the initiation stage of macroautophagy/autophagy using atg knockout (KO) cells and demonstrated that the ULK complex is recruited to 2 distinct membranes: the ER membrane and ATG9A-positive autophagosome precursors. We have also identified phosphatidylinositol synthase (PIS)-enriched ER subdomains as the initiation site of autophagosome formation. Based on these findings, we propose that the ULK complex, the PIS-enriched ER subdomain, and ATG9A vesicles together initiate autophagosome formation...
August 17, 2017: Autophagy
https://www.readbyqxmd.com/read/28813193/local-detection-of-ptdins3p-at-autophagosome-biogenesis-membrane-platforms
#10
Anna Chiara Nascimbeni, Patrice Codogno, Etienne Morel
Phosphatidylinositol 3-phosphate (PtdIns3P) is a key player of membrane trafficking regulation, mostly synthesized by the PIK3C3 lipid kinase. The presence of PtdIns3P on endosomes has been demonstrated; however, the role and dynamics of the pool of PtdIns3P dedicated to macroautophagy/autophagy remains elusive. Here we addressed this question by studying the mobilization of PtdIns3P in time and space during autophagosome biogenesis. We compared different dyes known to specifically detect PtdIns3P by fluorescence microscopy analysis, based on PtdIns3P-binding FYVE and PX domains, and show that these transfected dyes induce defects in endosomal dynamics as well as artificial and sustained autophagosome formation...
August 16, 2017: Autophagy
https://www.readbyqxmd.com/read/28813181/pathway-choice-between-proteasomal-and-autophagic-degradation
#11
Kefeng Lu, Fabian den Brave, Stefan Jentsch
Efficient degradation of abnormal or aggregated proteins is crucial to protect the cell against proteotoxic stress. Selective targeting and disposal of such proteins usually occurs in a ubiquitin-dependent manner by proteasomes and macroautophagy/autophagy. Whereas proteasomes are efficient in degrading abnormal soluble proteins, protein aggregates are typically targeted for degradation by autophagic vesicles. Both processes require ubiquitin-binding receptors, which are targeted to proteasomes via ubiquitin-like domains or to phagophores (the precursors to autophagosomes) via Atg8/LC3 binding motifs, respectively...
August 16, 2017: Autophagy
https://www.readbyqxmd.com/read/28813180/inflammatory-signaling-cascades-and-autophagy-in-cancer
#12
Teresa Monkkonen, Jayanta Debnath
Tumor-associated inflammation is predictive of poor prognosis and drives a variety of tumorigenic phenotypes, including tumor proliferation and survival, angiogenesis, invasiveness, and metastasis. Here, we review mammalian data addressing the interaction of macroautophagy/autophagy with key signaling cascades associated with tumor inflammation. Although our understanding of this area remains incomplete, certain inflammatory pathways have emerged as important mediators of the crosstalk between autophagy and inflammation in tumors...
August 16, 2017: Autophagy
https://www.readbyqxmd.com/read/28813167/lipophagy-maintains-energy-homeostasis-in-the-kidney-proximal-tubule-during-prolonged-starvation
#13
Satoshi Minami, Takeshi Yamamoto, Yoshitsugu Takabatake, Atsushi Takahashi, Tomoko Namba, Jun Matsuda, Tomonori Kimura, Jun-Ya Kaimori, Isao Matsui, Takayuki Hamano, Hiroaki Takeda, Masatomo Takahashi, Yoshihiro Izumi, Takeshi Bamba, Taiji Matsusaka, Fumio Niimura, Yoshitaka Isaka
Macroautophagy/autophagy is a self-degradation process that combats starvation. Lipids are the main energy source in kidney proximal tubular cells (PTCs). During starvation, PTCs increase fatty acid (FA) uptake, form intracellular lipid droplets (LDs), and hydrolyze them for use. The involvement of autophagy in lipid metabolism in the kidney remains largely unknown. Here, we investigated the autophagy-mediated regulation of renal lipid metabolism during prolonged starvation using PTC-specific Atg5-deficient (atg5-TSKO) mice and an in vitro serum starvation model...
August 16, 2017: Autophagy
https://www.readbyqxmd.com/read/28812939/removing-dysfunctional-mitochondria-from-axons-independent-of-mitophagy-under-pathophysiological-conditions
#14
Mei-Yao Lin, Xiu-Tang Cheng, Yuxiang Xie, Qian Cai, Zu-Hang Sheng
Chronic mitochondrial dysfunction has been implicated in major neurodegenerative diseases. Long-term cumulative pathological stress leads to axonal accumulation of damaged mitochondria. Therefore, the early removal of defective mitochondria from axons constitutes a critical step of mitochondrial quality control. We recently investigated the axonal mitochondrial response to mild stress in wild-type neurons and chronic mitochondrial defects in amyotrophic lateral sclerosis (ALS)- and Alzheimer disease (AD)-linked neurons...
August 16, 2017: Autophagy
https://www.readbyqxmd.com/read/28812437/autophagy-induced-kdr-vegfr-2-activation-promotes-the-formation-of-vasculogenic-mimicry-by-glioma-stem-cells
#15
Hai-Bo Wu, Shuai Yang, Hai-Yan Weng, Qian Chen, Xi-Long Zhao, Wen-Juan Fu, Qin Niu, Yi-Fang Ping, Ji Ming Wang, Xia Zhang, Xiao-Hong Yao, Xiu-Wu Bian
Antiangiogenesis with bevacizumab, an antibody against vascular endothelial growth factor (VEGF), has been used for devascularization to limit the growth of malignant glioma. However, the benefits are transient due to elusive mechanisms underlying resistance to the antiangiogenic therapy. Glioma stem cells (GSCs) are capable of forming vasculogenic mimicry (VM), an alternative microvascular circulation independent of VEGF-driven angiogenesis. Herein, we report that the formation of VM was promoted by bevacizumab-induced macroautophagy/autophagy in GSCs, which was associated with tumor resistance to antiangiogenic therapy...
August 16, 2017: Autophagy
https://www.readbyqxmd.com/read/28812433/regulation-of-sqstm1-p62-via-uba-domain-ubiquitination-and-its-role-in-disease
#16
YouJin Lee, Conrad C Weihl
Macroautophagy/autophagy can be a selective degradative process via the utilization of various autophagic receptor proteins. Autophagic receptors selectively recognize ubiquitinated cargoes and deliver them to phagophores, the precursors to autophagosomes, for their degradation. For example, SQSTM1/p62 directly binds to ubiquitinated protein aggregates via its UBA domain and sequesters them into inclusion bodies via its PB1 domain. SQSTM1also interacts with phagophores via its LC3-interacting (LIR) motif. However, a regulatory mechanism for autophagic receptors is not yet understood...
August 16, 2017: Autophagy
https://www.readbyqxmd.com/read/28806150/the-puncta-enigma
#17
Daniel J Klionsky
This Editor's Corner may sound like the title of a mystery novel, but it actually reflects a question I have about the puncta articles that appear in Autophagy. In particular, I am surprised by the number of solicitations sent out for puncta that are either ignored, or, less frequently, declined. It is not that I expect the principal investigator (PI) to find the invitation to write a punctum undeniably attractive. Rather, it is the unilateral decision that it is not worthwhile for graduate students or postdocs who performed the work---and likely wrote at least the first draft of the paper---to write the punctum...
August 14, 2017: Autophagy
https://www.readbyqxmd.com/read/28806139/mask-mitigates-mapt-and-fus-induced-degeneration-by-enhancing-autophagy-through-lysosomal-acidification
#18
Mingwei Zhu, Sheng Zhang, Xiaolin Tian, Chunlai Wu
Accumulation of intracellular misfolded or damaged proteins is associated with both normal aging and late-onset degenerative diseases. Two cellular clearance mechanisms, the ubiquitin-proteasome system (UPS) and the macroautophagy/autophagy-lysosomal pathway, work in concert to degrade harmful protein aggregates and maintain protein homeostasis. Here we show that Mask, an Ankyrin-repeat and KH-domain containing protein, plays a key role in promoting autophagy flux and mitigating degeneration caused by protein aggregation or impaired UPS function...
August 14, 2017: Autophagy
https://www.readbyqxmd.com/read/28806138/lipid-droplets-and-lipotoxicity-during-autophagy
#19
Truc B Nguyen, James A Olzmann
Lipid droplets (LDs) are neutral lipid storage organelles that provide a rapidly accessible source of fatty acids (FAs) for energy during periods of nutrient deprivation. Surprisingly, lipids released by the macroautophagic/autophagic breakdown of membranous organelles are packaged and stored in new LDs during periods of prolonged starvation. Why cells would store FAs during an energy crisis was unknown. In our recent study, we demonstrated that FAs released during MTORC1-regulated autophagy are selectively channeled by DGAT1 (diacylglycerol O-acyltransferase 1) into triacylglycerol (TAG)-rich LDs...
August 14, 2017: Autophagy
https://www.readbyqxmd.com/read/28806134/ilir-viral-a-web-resource-for-lir-motif-containing-proteins-in-viruses
#20
Anne-Claire Jacomin, Siva Samavedam, Hannah Charles, Ioannis P Nezis
Macroautophagy/autophagy has been shown to mediate the selective lysosomal degradation of pathogenic bacteria and viruses (xenophagy), and to contribute to the activation of innate and adaptative immune responses. Autophagy can serve as an antiviral defense mechanism but also as a pro-viral process during infection. Atg8-family proteins play a central role in the autophagy process due to their ability to interact with components of the autophagy machinery as well as selective autophagy receptors and adaptor proteins...
August 14, 2017: Autophagy
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