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Liang Ouyang, Lan Zhang, Leilei Fu, Bo Liu
ULK1 (unc-51 like autophagy activating kinase 1) is well known to be required to initiate the macroautophagy/autophagy process, and thus activation of ULK1-modulating autophagy/autophagy-associated cell death (ACD) may be a possible therapeutic strategy in triple negative breast cancer (TNBC). Here, our integrated The Cancer Genome Atlas (TCGA) dataset, tissue microarray-based analyses and multiple biological evaluations together demonstrate a new small-molecule activator of ULK1 for better understanding of how ULK1, the mammalian homolog of yeast Atg1, as a potential drug target can regulate ACD by the ULK complex (ULK1-ATG13-RB1CC1/FIP200-ATG101), as well as other possible ULK1 interactors, including ATF3, RAD21 and CASP3/caspase3 in TNBC...
February 6, 2017: Autophagy
Jiefei Geng, Daniel J Klionsky
Macroautophagy/autophagy remains a rapidly advancing research topic, and there continues to be a need for constantly evolving methodology to investigate this pathway at each individual step. Accordingly, new assays to measure autophagic flux in a robust and reliable manner are essential to understand the mechanism and physiological roles of autophagy. Kaizuka et al. recently reported a new fluorescence probe, GFP-LC3-RFP-LC3δG to directly demonstrate autophagic flux without being combined with lysosomal inhibitors (see the punctum in this issue of the journal)...
February 6, 2017: Autophagy
Benjamin Scott Padman, Thanh Ngoc Nguyen, Michael Lazarou
It has been widely assumed that Atg8 family LC3/GABARAP proteins are essential for the formation of autophagosomes during macroautophagy/autophagy, and the sequestration of cargo during selective autophagy. However, there is little direct evidence on the functional contribution of these proteins to autophagosome biogenesis in mammalian cells. To dissect the functions of LC3/GABARAPs during starvation-induced autophagy and PINK1-PARK2/Parkin-dependent mitophagy, we utilized CRISPR/Cas9 gene editing to generate knockouts of the LC3 and GABARAP subfamilies, and all 6 Atg8 family proteins in HeLa cells...
February 6, 2017: Autophagy
Yoshitsugu Takabatake, Takeshi Yamamoto, Yoshitaka Isaka
Excessive fat intake can lead to cellular injury and inflammation (termed lipotoxicity), but studies on lipid metabolism in the kidney have been scarce. We recently identified a novel mechanism of lipotoxicity in the kidney proximal tubules especially focusing on the effect of lipid overload on lysosomal function and autophagic activity. Lipid overload basically stimulates macroautophagy/autophagy for renovation of the plasma and organelle membranes, which plays an essential role in maintaining the integrity of proximal tubules...
February 6, 2017: Autophagy
Sandra Kissing, Sönke Rudnik, Markus Damme, Renate Lüllmann-Rauch, Atsuhiro Ichihara, Uwe Kornak, Eeva-Liisa Eskelinen, Sabrina Jabs, Jörg Heeren, Jef K De Brabander, Albert Haas, Paul Saftig
The vacuolar-type H(+)-translocating ATPase (v-H(+)-ATPase) has been implicated in the amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (MTORC1), an important regulator of macroautophagy. To reveal the mechanistic links between the v-H(+)-ATPase and MTORC1 we destablilized v-H(+)-ATPase complexes in mouse liver cells by induced deletion of the essential chaperone ATP6AP2. ATP6AP2-mutants are characterized by massive accumulation of endocytic and autophagic vacuoles in hepatocytes...
January 27, 2017: Autophagy
Juan Liu, Hailong Wang, Jinyan Gu, Tingjuan Deng, Zhuangchuan Yuan, Boli Hu, Yunbin Xu, Yan Yan, Jie Zan, Min Liao, Erin DiCaprio, Jianrong Li, Shuo Su, Jiyong Zhou
Autophagy is an essential component of host immunity and utilized by viruses for survival. However, the autophagy signaling pathways involved in virus replication are poorly documented. Here, we observed that rabies virus (RABV) infection triggered intracellular autophagosome accumulation and results in incomplete autophagy by inhibiting autophagy flux. Subsequently, we found that RABV infection induced the reduction of CASP2/caspase 2 and the activation of AMP-activated protein kinase (AMPK)-AKT-MTOR (mechanistic target of rapamycin) and AMPK-MAPK (mitogen-activated protein kinase) pathways...
January 27, 2017: Autophagy
Yongfei Hu, Yan Huang, Ying Yi, Hongwei Wang, Bing Liu, Jia Yu, Dong Wang
Accumulating evidence has demonstrated that macroautophagy/autophagy plays an essential role in self-renewal and differentiation in embryonic hematopoiesis. Here, according to the RNA sequencing datasets of 5 population cells related to hematopoietic stem cell (HSC) formation during mouse embryogenesis (endothelial cells, PTPRC/CD45(-) and PTPRC/CD45(+) pre-HSCs in the E11 aorta-gonad-mesonephros (AGM) region, mature HSCs in E12 and E14 fetal liver), we explored the dynamic expression of mouse autophagy-related genes in this course at the single-cell level...
January 27, 2017: Autophagy
Feng-Jun Li, Zhi-Shen Xu, Andy D S Soo, Zhao-Rong Lun, Cynthia Y He
Autophagy is a catabolic cellular process required to maintain protein synthesis, energy production and other essential activities in starved cells. While the exact nutrient sensor(s) is yet to be identified, deprivation of amino acids, glucose, growth factor and other nutrients can serve as metabolic stimuli to initiate autophagy in higher eukaryotes. In the early-branching unicellular parasite Trypanosoma brucei, which can proliferate as procyclic form (PCF) in the tsetse fly or as bloodstream form (BSF) in animal hosts, autophagy is robustly triggered by amino acid deficiency but not by glucose depletion...
January 25, 2017: Autophagy
Longhao Sun, Limei Hu, David Cogdell, Li Lu, Chao Gao, Weijun Tian, Zhixiang Zhang, Ya'an Kang, Jason B Fleming, Wei Zhang
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and lethal cancer. The role of autophagy in the pathobiology of PDAC is intricate, with opposing functions manifested in different cellular contexts. MIR506 functions as a tumor suppressor in many cancer types through the regulation of multiple pathways. In this study, we hypothesized that MIR506 exerted a tumor suppression function in PDAC by inducing autophagy-related cell death. Our results provided evidence that downregulation of MIR506 expression was associated with disease progression in human PDAC...
January 25, 2017: Autophagy
Lijie Feng, Jin Zhang, Na Zhu, Qian Ding, Xiaojie Zhang, Jishuang Yu, Weimin Qiang, Zhetao Zhang, Yuyang Ma, Dake Huang, Yujun Shen, Shengyun Fang, Yifan Yu, Haiping Wang, Yuxian Shen
SERPINA1/AAT/alpha-1-antitrypsin (serpin family A member 1) deficiency (SERPINA1/ AAT-D) is an autosomal recessive disorder characterized by the retention of misfolded SERPINA1/AAT in the endoplasmic reticulum (ER) of hepatocytes and a significant reduction of serum SERPINA1/AAT level. The Z variant of SERPINA1/AAT, containing a Glu342Lys (E342K) mutation (SERPINA1(E342K)/ATZ), the most common form of SERPINA1/AAT-D, is prone to misfolding and polymerization, which retains it in the ER of hepatocytes and leads to liver injury...
January 25, 2017: Autophagy
Victoria Cohen-Kaplan, Aaron Ciechanover, Ido Livneh
Ubiquitin (Ub) is a small protein (8 kDa) found in all eukaryotic cells, which is conjugated covalently to numerous proteins, tagging them for recognition by a downstream effector. One of the best characterized functions of Ub is targeting proteins for either selective degradation by the proteasome, or for bulk degradation by the autophagy-lysosome system. The executing arm of the UPS is the 26S proteasome, a large multi-catalytic complex. While much is known about the synthesis and assembly of the proteasome's subunits, the mechanism(s) underlying its removal has remained obscure, similar to that of many other components of the ubiquitin-proteasome system...
January 25, 2017: Autophagy
Chao Sun, Xiongxiong Liu, Cuixia Di, Zhenhua Wang, Xiangquan Mi, Yang Liu, Qiuyue Zhao, Aihong Mao, Weiqiang Chen, Lu Gan, Hong Zhang
During the process of oxidative phosphorylation, protons are pumped into the mitochondrial intermembrane space to establish a mitochondrial membrane potential (MMP). The electrochemical gradient generated allows protons to return to the matrix through the ATP synthase complex and generates ATP in the process. MitoQ is a lipophilic cationic drug that is adsorbed to the inner mitochondrial membrane; however, the cationic moiety of MitoQ remains in the intermembrane space. We found that the positive charges in MitoQ inhibited the activity of respiratory chain complexes I, III, and IV, reduced proton production, and decreased oxygen consumption...
January 25, 2017: Autophagy
Hideaki Morishita, Takeshi Kaizuka, Yutaro Hama, Noboru Mizushima
Macroautophagy is a catabolic process that delivers cytoplasmic components via the autophagosome to lysosomes for degradation. Measuring autophagic activity is critical to dissect molecular mechanisms and functions of autophagy but remains challenging due to the lack of a definitive method. We have recently developed a new fluorescent probe, GFP-LC3-RFP-LC3ΔG, to assess autophagic flux. Upon intracellular expression, the probe is cleaved by ATG4 family proteases into equimolar amounts of GFP-LC3 and RFP-LC3ΔG...
January 25, 2017: Autophagy
Darius Ebrahimi-Fakhari, Afshin Saffari, Lara Wahlster, Mustafa Sahin
Constitutive activation of the MTOR pathway is a key feature of defects in the tuberous sclerosis complex and other genetic neurodevelopmental diseases, collectively referred to as MTORopathies. MTORC1 hyperactivity promotes anabolic cell functions such as protein synthesis, yet at the same time catabolic processes such as macroautophagy/autophagy are suppressed. Mitochondria are major substrates of autophagy; however, their role in MTORopathies remains largely undefined. Here, we review our recent study showing that several aspects of mitochondrial function, dynamics and turnover are critically impaired in neuronal models of TSC...
January 25, 2017: Autophagy
Dorotea Fracchiolla, Justyna Sawa-Makarska, Sascha Martens
Selective macroautophagy/autophagy mediates the selective delivery of cytoplasmic cargo material via autophagosomes into the lytic compartment for degradation. This selectivity is mediated by cargo receptor molecules that link the cargo to the phagophore (the precursor to the autophagosome) membrane via their simultaneous interaction with the cargo and Atg8 proteins on the membrane. Atg8 proteins are attached to membrane in a conjugation reaction and the cargo receptors bind them via short peptide motifs called Atg8-interacting motifs/LC3-interacting regions (AIMs/LIRs)...
January 25, 2017: Autophagy
Yuhei Mizunoe, Yuka Sudo, Naoyuki Okita, Hidenori Hiraoka, Kentaro Mikami, Tomohiro Narahara, Arisa Negishi, Miki Yoshida, Rikako Higashibata, Shukoh Watanabe, Hiroki Kaneko, Daiki Natori, Takuma Furuichi, Hiromine Yasukawa, Masaki Kobayashi, Yoshikazu Higami
Whether obesity accelerates or suppresses autophagy in adipose tissue is still debatable. To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, we focused on lysosomal function, protease maturation and activity, both in vivo and in vitro. First, we showed that autophagosome formation was accelerated, but autophagic clearance was impaired in obese adipose tissue. We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obese adipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced...
January 25, 2017: Autophagy
Nena Matscheko, Peter Mayrhofer, Thomas Wollert
Macroautophagy delivers cytoplasmic material to lysosomal/vacuolar compartments for degradation. Conserved multi-subunit complexes, composed of autophagy related (Atg) proteins, initiate the formation of membrane precursors, termed phagophores. Under physiological conditions these cup- shaped structures can capture cytoplasmic material highly selectively. Starvation or cytotoxic stresses, however, initiate the formation of much larger phagophores to enclose cytoplasm nonselectively. The biogenesis of nonselective autophagosomes is initiated by the hierarchical assembly of the Atg1 kinase complex and the recruitment of Atg9 vesicles at the phagophore assembly site (PAS)...
January 25, 2017: Autophagy
Ji Eun Jang, Ju-In Eom, Hoi-Kyung Jeung, June-Won Cheong, Jung Yeon Lee, Jin Seok Kim, Yoo Hong Min
Bromodomain and extraterminal domain (BET) inhibitors are promising epigenetic agents for the treatment of various subsets of acute myeloid leukemia (AML). However, the resistance of leukemia stem cells (LSCs) to BET inhibitors remains a major challenge. In this study, we evaluated the mechanisms underlying LSC resistance to the BET inhibitor JQ1. We evaluated the levels of apoptosis and macroautophagy/autophagy induced by JQ1 in LSC-like leukemia cell lines and primary CD34(+) CD38(-) leukemic blasts obtained from AML cases with normal karyotype without recurrent mutations...
January 24, 2017: Autophagy
Tobias Eisenberg, Mahmoud Abdellatif, Andreas Zimmermann, Sabrina Schroeder, Tobias Pendl, Alexandra Harger, Slaven Stekovic, Julia Schipke, Christoph Magnes, Albrecht Schmidt, Christoph Ruckenstuhl, Christopher Dammbrueck, Angelina S Gross, Viktoria Herbst, Didac Carmona-Gutierrez, Federico Pietrocola, Thomas R Pieber, Stephan J Sigrist, Wolfgang A Linke, Christian Mühlfeld, Junichi Sadoshima, Joern Dengjel, Stefan Kiechl, Guido Kroemer, Simon Sedej, Frank Madeo
Loss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the development of cardiovascular disease. Dietary spermidine elicits cardioprotective effects in aged mice through enhancing cardiac autophagy and mitophagy. In salt-sensitive rats, spermidine supplementation also delays the development of hypertensive heart disease, coinciding with reduced arterial blood pressure...
January 24, 2017: Autophagy
Hana Popelka, Daniel J Klionsky
Atg13 is an essential subunit of the Atg1 autophagy initiation complex in yeast and its mammalian counterpart, ATG13, is indispensable for autophagy induction by the ULK1 complex. The N terminus of the protein folds into a HORMA domain, an architecture that has been revealed by crystallography. (1-4) In human cells, the ATG13 HORMA domain interacts directly with ATG14, a subunit of the class III phosphatidylinositol 3-kinase complex. (5) In budding yeast, the HORMA of Atg13 recruits Atg14, but a direct interaction remains to be proven...
January 24, 2017: Autophagy
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