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Autophagy

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https://www.readbyqxmd.com/read/28513333/atg9a-deficiency-causes-axon-specific-lesions-including-neuronal-circuit-dysgenesis
#1
Junji Yamaguchi, Chigure Suzuki, Tomohisa Nanao, Soichirou Kakuta, Kentarou Ozawa, Isei Tanida, Tatsuya Saitoh, Takehiko Sunabori, Masaaki Komatsu, Keiji Tanaka, Shigeki Aoki, Kenji Sakimura, Yasuo Uchiyama
Conditional knockout mice for Atg9a, specifically in brain tissue, were generated to understand the roles of ATG9A in the neural tissue cells. The mice were born normally, but half of them died within one week, and none lived beyond 4 weeks of age. SQSTM1/p62 and NBR1, receptor proteins for selective autophagy, together with ubiquitin, accumulated in Atg9a-deficient neurosoma at postnatal day 15 (P15), indicating an inhibition of autophagy, whereas these proteins were significantly decreased at P28, as evidenced by immunohistochemistry, electron microscopy and western blot...
May 17, 2017: Autophagy
https://www.readbyqxmd.com/read/28513279/w09-a-novel-autophagy-enhancer-induces-autophagy-dependent-cell-apoptosis-via-activation-of-the-egfr-mediated-ras-raf1-map2k-mapk1-3-pathway
#2
Pinghu Zhang, Zuguo Zheng, Li Ling, Xiaohui Yang, Ni Zhang, Xue Wang, Maozhi Hu, Yu Xia, Yiwen Ma, Haoran Yang, Yunyi Wang, Hongqi Liu
The EGFR (epidermal growth factor receptor) signaling pathway is frequently deregulated in many malignancies. Therefore, targeting the EGFR pathway is regarded as a promising strategy for anticancer drug discovery. Herein, we identified a 2-amino-nicotinonitrile compound (w09) as a novel autophagy enhancer, which potently induced macroautophagy/autophagy and consequent apoptosis in gastric cancer cells. Mechanistic studies revealed that EGFR-mediated activation of the RAS-RAF1-MAP2K-MAPK1/3 signaling pathway played a critical role in w09-induced autophagy and apoptosis of gastric cancer cells...
May 17, 2017: Autophagy
https://www.readbyqxmd.com/read/28486053/active-interaction-mapping-as-a-tool-to-elucidate-hierarchical-functions-of-biological-processes
#3
Jean-Claude Farré, Michael Kramer, Trey Ideker, Suresh Subramani
Increasingly, various 'omics data are contributing significantly to our understanding of novel biological processes, but it has not been possible to iteratively elucidate hierarchical functions in complex phenomena. We describe a general systems biology approach called Active Interaction Mapping (AI-MAP), which elucidates the hierarchy of functions for any biological process. Existing and new 'omics datasets can be iteratively added to create and improve hierarchical models which enhance our understanding of particular biological processes...
May 9, 2017: Autophagy
https://www.readbyqxmd.com/read/28486049/march5-fundc1-axis-fine-tunes-hypoxia-induced-mitophagy
#4
Ziheng Chen, Sami Siraj, Lei Liu, Quan Chen
Mitophagy is responsible for removal of damaged mitochondria and is therefore a fundamental process in mitochondrial quality control. Both ubiquitin-dependent and receptor-dependent pathways are considered to mediate mitophagy. These distinct mechanisms may be activated in response to distinct mitochondrial stresses. An intriguing question is whether and how cross-talk occurs between the distinct pathways to coordinate mitophagy. We have uncovered a striking piece of evidence to demonstrate that the mitophagy receptor FUNDC1 is a substrate of MARCH5, a mitochondrially localized E3 ubiquitin ligase...
May 9, 2017: Autophagy
https://www.readbyqxmd.com/read/28486006/protein-kinase-activity-of-the-glycolytic-enzyme-pgk1-regulates-autophagy-to-promote-tumorigenesis
#5
Xu Qian, Xinjian Li, Zhimin Lu
Macroautophagy/autophagy is a cellular defense response to stress conditions and is crucial for cell homeostasis maintenance. However, the precise mechanism underlying autophagy initiation, especially in response to glutamine deprivation and hypoxia, remains to be explored. We recently discovered that PGK1 (phosphoglycerate kinase 1), a glycolytic enzyme, functions as a protein kinase, phosphorylating BECN1/Beclin1 to initiate autophagy. Under glutamine deprivation or hypoxia stimulation, PGK1 is acetylated at K388 by NAA10/ARD1 in an MTOR-inhibition-dependent manner, leading to the interaction between PGK1 and BECN1 and the subsequent phosphorylation of BECN1 at S30 by PGK1...
May 9, 2017: Autophagy
https://www.readbyqxmd.com/read/28453381/degradation-of-protein-translation-machinery-by-amino-acid-starvation-induced-macroautophagy
#6
Christine Gretzmeier, Sven Eiselein, Gregory R Johnson, Rudolf Engelke, Heike Nowag, Mostafa Zarei, Victoria Küttner, Andrea C Becker, Kristoffer T G Rigbolt, Maria Høyer-Hansen, Jens S Andersen, Christian Münz, Robert F Murphy, Jörn Dengjel
Macroautophagy is regarded as a nonspecific bulk degradation process of cytoplasmic material within the lysosome. However, the process has mainly been studied by nonspecific bulk degradation assays using radiolabeling. In the present study we monitor protein turnover and degradation by global, unbiased approaches relying on quantitative mass spectrometry-based proteomics. Macroautophagy is induced by rapamycin treatment, and by amino acid and glucose starvation in differentially, metabolically labeled cells...
April 28, 2017: Autophagy
https://www.readbyqxmd.com/read/28441084/the-emergence-of-noncoding-rnas-as-heracles-in-autophagy
#7
Jian Zhang, Peiyuan Wang, Lin Wan, Shouping Xu, Da Pang
Macroautophagy/autophagy is a catabolic process that is widely found in nature. Over the past few decades, mounting evidence has indicated that noncoding RNAs, ranging from small noncoding RNAs to long noncoding RNAs (lncRNAs) and even circular RNAs (circRNAs), mediate the transcriptional and post-transcriptional regulation of autophagy-related genes by participating in autophagy regulatory networks. The differential expression of noncoding RNAs affects autophagy levels at different physiological and pathological stages, including embryonic proliferation and differentiation, cellular senescence, and even diseases such as cancer...
April 25, 2017: Autophagy
https://www.readbyqxmd.com/read/28441075/autophagy-and-kidney-inflammation
#8
Tomonori Kimura, Yoshitaka Isaka, Tamotsu Yoshimori
Inflammation plays a pivotal role in pathophysiological processes of kidney diseases. Macroautophagy/autophagy plays multiple roles in inflammatory responses, and the regulation of inflammation by autophagy has great potential as a treatment for damaged kidneys. A growing body of evidence suggests autophagy protects kidney from versatile kidney inflammatory insults, including those that are acute, chronic, metabolic, and aging-related. Noteworthy is that, in kidney, mitophagy is active, and damaged lysosomes are removed by autophagy...
April 25, 2017: Autophagy
https://www.readbyqxmd.com/read/28441070/the-thr300ala-variant-of-atg16l1-is-associated-with-decreased-risk-of-brain-metastasis-in-patients-with-non-small-cell-lung-cancer
#9
Qian-Xia Li, Xiao Zhou, Ting-Ting Huang, Yang Tang, Bo Liu, Ping Peng, Li Sun, Yi-Hua Wang, Xiang-Lin Yuan
Non-small cell lung cancer (NSCLC) often metastasizes to the brain, but identifying which patients will develop brain metastases (BM) is difficult. Macroautophagy/autophagy is critical for cancer initiation and progression. We hypothesized that genetic variants of autophagy-related genes may affect brain metastases (BM) in NSCLC patients. We genotyped 16 single nucleotide polymorphisms (SNPs) in 7 autophagy-related (ATG) genes (ATG3, ATG5, ATG7, ATG10, ATG12, ATG16L1, and MAP1LC3/LC3) by using DNA from blood samples of 323 NSCLC patients...
April 25, 2017: Autophagy
https://www.readbyqxmd.com/read/28402699/inhibition-of-retrograde-transport-modulates-misfolded-protein-accumulation-and-clearance-in-motoneuron-diseases
#10
Riccardo Cristofani, Valeria Crippa, Paola Rusmini, Maria Elena Cicardi, Marco Meroni, Nausicaa V Licata, Gessica Sala, Elisa Giorgetti, Christopher Grunseich, Mariarita Galbiati, Margherita Piccolella, Elio Messi, Carlo Ferrarese, Serena Carra, Angelo Poletti
Motoneuron diseases, like spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS), are associated with proteins that because of gene mutation or peculiar structures, acquire aberrant (misfolded) conformations toxic to cells. To prevent misfolded protein toxicity, cells activate a protein quality control (PQC) system composed of chaperones and degradative pathways (proteasome and autophagy). Inefficient activation of the PQC system results in misfolded protein accumulation that ultimately leads to neuronal cell death, while efficient macroautophagy/autophagy-mediated degradation of aggregating proteins is beneficial...
April 12, 2017: Autophagy
https://www.readbyqxmd.com/read/28402693/heparan-sulfate-proteoglycans-regulate-autophagy-in-drosophila
#11
Claire E Reynolds-Peterson, Na Zhao, Jie Xu, Taryn M Serman, Jielin Xu, Scott B Selleck
Heparan sulfate-modified proteoglycans (HSPGs) are important regulators of signaling and molecular recognition at the cell surface and in the extracellular space. Disruption of HSPG core proteins, HS-synthesis, or HS-degradation can have profound effects on growth, patterning, and cell survival. The Drosophila neuromuscular junction provides a tractable model for understanding the activities of HSPGs at a synapse that displays developmental and activity-dependent plasticity. Muscle cell-specific knockdown of HS biosynthesis disrupted the organization of a specialized postsynaptic membrane, the subsynaptic reticulum (SSR), and affected the number and morphology of mitochondria...
April 12, 2017: Autophagy
https://www.readbyqxmd.com/read/28368722/tumor-cell-intrinsic-cd274-pd-l1-a-novel-metabolic-balancing-act-with-clinical-potential
#12
Curtis A Clark, Harshita B Gupta, Tyler J Curiel
Tumor expression of the immune co-signaling molecule CD274/PD-L1 was originally described as impeding antitumor immunity by direct engagement of its receptor, PDCD1/PD-1, on antitumor T cells. Melanoma-intrinsic PDCD1 was recently shown to promote tumor growth and MTOR signals in cooperation with tumor CD274, and sarcoma-intrinsic CD274 signaling promotes glucose metabolism to impede antitumor immunity. Our recent report shows that tumor cell-intrinsic CD274 promotes MTORC1 signaling in mouse melanoma and mouse and human ovarian cancer, inhibits autophagy and sensitizes some tumors to clinically available pharmacological autophagy inhibitors and confers resistance to MTOR inhibitors...
April 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28368721/cellular-and-molecular-mechanism-for-secretory-autophagy
#13
Tomonori Kimura, Jingyue Jia, Aurore Claude-Taupin, Suresh Kumar, Seong Won Choi, Yuexi Gu, Michal Mudd, Nicolas Dupont, Shanya Jiang, Ryan Peters, Farzin Farzam, Ashish Jain, Keith A Lidke, Christopher M Adams, Terje Johansen, Vojo Deretic
Macroautophagy/autophagy plays a role in unconventional secretion of leaderless cytosolic proteins. Whether and how secretory autophagy diverges from conventional degradative autophagy is unclear. We have shown that the prototypical secretory autophagy cargo IL1B/IL-1β (interleukin 1 β) is recognized by TRIM16, and that this first to be identified secretory autophagy receptor interacts with the R-SNARE SEC22B to jointly deliver cargo to the MAP1LC3B-II-positive sequestration membranes. Cargo secretion is unaffected by knockdowns of STX17, a SNARE catalyzing autophagosome-lysosome fusion as a prelude to cargo degradation...
April 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28368693/galectins-and-trims-directly-interact-and-orchestrate-autophagic-response-to-endomembrane-damage
#14
Suresh Kumar, Santosh Chauhan, Ashish Jain, Marisa Ponpuak, Seong Won Choi, Michal Mudd, Ryan Peters, Michael A Mandell, Terje Johansen, Vojo Deretic
Macroautophagy/autophagy is a homeostatic process delivering cytoplasmic targets, including damaged organelles, to lysosomes for degradation; however, it is not completely understood how compromised endomembranes are recognized by the autophagic apparatus. We have described previously that the TRIM family of proteins act as receptors for selective autophagy. In this study we uncovered the property of TRIMs to directly interact with members of the family of cytosolic lectins termed galectins. Galectins patrol the cytoplasm and recognize compromised membranes...
April 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28368682/stress-dependent-opposing-roles-for-mitophagy-in-aging-of-the-ascomycete-podospora-anserina
#15
Laura Knuppertz, Verena Warnsmann, Andrea Hamann, Carolin Grimm, Heinz D Osiewacz
Mitochondrial dysfunction is causatively linked to organismal aging and the development of degenerative diseases. Here we describe stress-dependent opposing roles of mitophagy, the selective autophagic degradation of mitochondria, in aging and life-span control. We report that the ablation of the mitochondrial superoxide dismutase which is involved in reactive oxygen species (ROS) balancing, does not affect life span of the fungal aging model Podospora anserina, although superoxide levels are strongly increased and complex I-dependent respiration is impaired...
April 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28350524/an-atf4-atg5-signaling-in-hypothalamic-pomc-neurons-regulates-obesity
#16
Yuzhong Xiao, Yalan Deng, Feixiang Yuan, Tingting Xia, Hao Liu, Zhigang Li, Shanghai Chen, Zhixue Liu, Hao Ying, Yi Liu, Qiwei Zhai, Feifan Guo
ATF4 (activating transcription factor 4) is an important transcription factor that has many biological functions, while its role in hypothalamic POMC (pro-opiomelanocortin-α) neurons in the regulation of energy homeostasis has not been explored. We recently discovered that mice with an Atf4 deletion specific to POMC neurons (PAKO mice) are lean and have higher energy expenditure. Furthermore, these mice are resistant to high-fat diet (HFD)-induced obesity and obesity-related metabolic disorders. Mechanistically, we found the expression of ATG5 (autophagy-related 5) is upregulated in POMC neurons of PAKO mice, and ATF4 regulates ATG5 expression by binding directly to its promoter...
March 28, 2017: Autophagy
https://www.readbyqxmd.com/read/28350209/b-cell-non-hodgkin-lymphoma-selective-vulnerability-to-pikfyve-inhibition
#17
Sophia Gayle, Sean Landrette, Neil Beeharry, Chris Conrad, Marylens Hernandez, Paul Beckett, Shawn M Ferguson, Tian Xu, Jonathan Rothberg, Henri Lichenstein
We identified the PIKFYVE inhibitor apilimod as a potent and selective cytotoxic agent against B-cell non-Hodgkin lymphoma (B-NHL). Our data robustly establish PIKFYVE as the target through which apilimod kills B-NHL cells and show that apilimod-induced death in B-NHL is mediated by broad disruption of lysosome homeostasis characterized by lysosomal swelling, TFEB nuclear translocation, impaired maturation of lysosomal enzymes and incomplete autophagosome clearance. Furthermore, through genome-wide CRISPR knockout screening, we identified specific lysosomal genes (TFEB, CLCN7, OSTM1 and SNX10) as critical determinants of apilimod-induced cytotoxicity...
March 28, 2017: Autophagy
https://www.readbyqxmd.com/read/28350199/a-novel-autophagy-modulator-6-bio-ameliorates-snca-%C3%AE-synuclein-toxicity
#18
S N Suresh, Aravinda K Chavalmane, Vidyadhara D J, Haorei Yarreiphang, Shashank Rai, Abhik Paul, James P Clement, Phalguni Anand Alladi, Ravi Manjithaya
Parkinson disease (PD) is a life-threatening neurodegenerative movement disorder with unmet therapeutic intervention. We have identified a small molecule autophagy modulator, 6-Bio that shows clearance of toxic SNCA/α-synuclein (a protein implicated in synucleopathies) aggregates in yeast and mammalian cell lines. 6-Bio induces autophagy and dramatically enhances autolysosome formation resulting in SNCA degradation. Importantly, neuroprotective function of 6-Bio as envisaged by immunohistology and behavior analyses in a preclinical model of PD where it induces autophagy in dopaminergic neurons of mice midbrain to clear toxic protein aggregates suggesting that it could be a potential therapeutic candidate for protein conformational disorders...
March 28, 2017: Autophagy
https://www.readbyqxmd.com/read/28333578/hormetic-heat-shock-and-hsf-1-overexpression-improve-c-elegans-survival-and-proteostasis-by-inducing-autophagy
#19
Caroline Kumsta, Malene Hansen
The cellular recycling process of macroautophagy/autophagy is an essential homeostatic system induced by various stresses, but it remains unclear how autophagy contributes to organismal stress resistance. In a recent study, we report that a mild and physiologically beneficial ("hormetic") heat shock as well as overexpression of the heat-shock responsive transcription factor HSF-1 systemically increases autophagy in C. elegans. Accordingly, we found HSF-1- and heat stress-inducible autophagy to be required for C...
March 23, 2017: Autophagy
https://www.readbyqxmd.com/read/28324658/mitochondrial-respiration-links-tor-complex-2-signaling-to-calcium-regulation-and-autophagy
#20
Ariadne Vlahakis, Nerea Lopez Muniozguren, Ted Powers
The Target of Rapamycin (TOR) kinase is a conserved regulator of cell growth and functions within 2 different protein complexes, TORC1 and TORC2, where TORC2 positively controls macroautophagy/autophagy during amino acid starvation. Under these conditions, TORC2 signaling inhibits the activity of the calcium-regulated phosphatase calcineurin and promotes the general amino acid control (GAAC) response and autophagy. Here we demonstrate that TORC2 regulates calcineurin by controlling the respiratory activity of mitochondria...
March 21, 2017: Autophagy
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