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Liam D Cassidy, Andrew Rj Young, Pedro A Pérez-Mancera, Birgit Nimmervoll, Adil Jaulim, Hung-Chang Chen, Dominick J O McIntyre, Rebecca Brais, Thomas Ricketts, Simon Pacey, Maike De La Roche, Richard J Gilbertson, David C Rubinsztein, Masashi Narita
Macroautophagy/autophagy is an evolutionarily conserved catabolic pathway whose modulation has been linked to diverse disease states, including age-associated disorders. Conventional and conditional whole-body knockout mouse models of key autophagy genes display perinatal death and lethal neurotoxicity, respectively, limiting their applications for in vivo studies. Here, we have developed an inducible shRNA mouse model targeting Atg5, allowing us to dynamically inhibit autophagy in vivo, termed ATG5i mice. The lack of brain-associated shRNA expression in this model circumvents the lethal phenotypes associated with complete autophagy knockouts...
July 12, 2018: Autophagy
Yiming Zhang, Cassandra B Higgins, Allyson L Mayer, Indira U Mysorekar, Babak B Razani, Mark J Graham, Paul W Hruz, Brian J DeBosch
The macroautophagy/autophagy-inducing disaccharide, trehalose, has been proposed to be a promising therapeutic agent against neurodegenerative and cardiometabolic diseases. We recently showed that trehalose attenuates hepatic steatosis in part by blocking hepatocyte glucose transport to induce hepatocyte autophagic flux. However, although every major demonstration of trehalose action invokes activating autophagic flux as its primary function, the mechanism of action of trehalose in whole-body energy metabolism remains poorly defined...
July 12, 2018: Autophagy
Nan Zhang, Xin Yang, Fengjie Yuan, Wei-Guo Zhu, Ying Zhao
Macroautophagy/autophagy is a unique protein degradation process by which intracellular materials are recycled for energy homeostasis. However, the metabolic status and energy source of autophagy-defective tumor cells is poorly understood. Here in this study, we found ATF4-dependent amino acid transporter (AAT) gene expression and amino acid uptake were increased in autophagy-deficient cells under conditions of Gln deprivation. Notably, inhibition of amino acid uptake reduced the viability of Gln-deprived autophagy-deficient cells, but not significantly in wild-type cells, suggesting the reliance of autophagy-deficient tumor cells on extracellular amino acid uptake...
July 11, 2018: Autophagy
Sho W Suzuki, Scott D Emr
No abstract text is available yet for this article.
July 11, 2018: Autophagy
Arishya Sharma, Turkeya Alswillah, Kamini Singh, Payel Chatterjee, Belinda Willard, Monica Venere, Matthew K Summers, Alexandru Almasan
Recent reports have made important revelations, uncovering direct regulation of DNA damage response (DDR)-associated proteins and chromatin ubiquitination (Ubn) by macroautophagy/autophagy. Here, we report a previously unexplored connection between autophagy and DDR, via a deubiquitnase (DUB), USP14. Loss of autophagy in prostate cancer cells led to unrepaired DNA double-strand breaks (DSBs) as indicated by persistent ionizing radiation (IR)-induced foci (IRIF) formation for γH2AFX, and decreased protein levels and IRIF formation for RNF168, an E3-ubiquitin ligase essential for chromatin Ubn and recruitment of critical DDR effector proteins in response to DSBs, including TP53BP1...
July 11, 2018: Autophagy
Wim Vandenberghe, Tom Cornelissen, Patrik Verstreken
Loss-of-function mutations in the genes encoding PRKN/parkin and PINK1 cause autosomal recessive Parkinson disease (PD). Seminal work in Drosophila revealed that loss of park/parkin and Pink1 causes prominent mitochondrial pathology in flight muscle and, to a lesser extent, in dopaminergic neurons. Subsequent studies in cultured mammalian cells discovered a crucial role for PRKN/PARK2 and PINK1 in selective macroautophagic removal of mitochondria (mitophagy). However, direct evidence for the existence of a PINK1-PRKN/PARK2-mediated mitophagy pathway in vivo is still scarce...
July 11, 2018: Autophagy
Abdul-Raouf Issa, Jun Sun, Céline Petitgas, Ana Mesquita, Amina Dulac, Marion Robin, Bertrand Mollereau, Andreas Jenny, Baya Chérif-Zahar, Serge Birman
The autophagy-lysosome pathway plays a fundamental role in the clearance of aggregated proteins and protection against cellular stress and neurodegenerative conditions. Alterations in autophagy processes, including macroautophagy and chaperone-mediated autophagy (CMA), have been described in Parkinson disease (PD). CMA is a selective autophagic process that depends on LAMP2A (Lysosomal associated membrane protein 2A), a mammal and bird-specific membrane glycoprotein that translocates cytosolic proteins containing a KFERQ-like peptide motif across the lysosomal membrane...
July 10, 2018: Autophagy
Guoshi Liu, Jingli Tao, Minghui Yang, Hao Wu, Teng Ma, Changjiu He, Menglong Chai, Xiaosheng Zhang, Jinlong Zhang, Fangrong Ding, Sutian Wang, Shoulong Deng, Kuanfeng Zhu, Yukun Song, Pengyun Ji, Haijun Liu, Zhengxing Lian
To explore the anti-inflammatory activity of endogenous produced melatonin, a melatonin-enriched animal model (goat) with AANAT transfer was successfully generated with somatic cell nuclear transfer (SCNT) technology. Basically, a pIRES2-EGFP-AANAT expression vector was constructed and was transferred into the female fetal fibroblast cells (FFCs) via electrotransfection and then the nuclear of the transgenic FFC was transferred to the eggs of the donor goats. The peripheral blood mononuclear cells (PBMCs) of the transgenic offspring expressed significantly higher levels of AANAT and melatonin synthetic function than those PBMCs from the wild-type (WT) animals...
July 9, 2018: Autophagy
Sriganesh Ramachandra Rao, Bruce A Pfeffer, Néstor Más Gómez, Lara A Skelton, Ueda Keiko, Janet R Sparrow, Aryn M Rowsam, Claire H Mitchell, Steven J Fliesler
Treatment of rats with the cholesterol pathway inhibitor AY9944 produces an animal model of Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive disease caused by defective cholesterol synthesis. This SLOS rat model undergoes progressive and irreversible degeneration of the neural retina, with associated pathological features of the retinal pigmented epithelium (RPE). Here, we provide further insights into the mechanism involved in the RPE pathology. In the SLOS rat model, markedly increased RPE apical autofluorescence is observed, compared to untreated animals, which correlates with increased levels of A2E and other bisretinoids...
July 6, 2018: Autophagy
Dae-Hee Lee, Daeho Kim, Sung Tae Kim, Soyeon Jeong, Jung Lim Kim, Sang Mi Shim, Ah Jung Heo, Xinxin Song, Zong Sheng Guo, David L Bartlett, Sang Cheul Oh, Junho Lee, Yoshiro Saito, Bo Yeon Kim, Yong Tae Kwon, Yong J Lee
Macroautophagy is induced under various stresses to remove cytotoxic materials, including misfolded proteins and their aggregates. These protein cargoes are collected by specific autophagic receptors such as SQSTM1/p62 (sequestosome 1) and delivered to phagophores for lysosomal degradation. To date, little is known about how cells sense and react to diverse stresses by inducing the activity of SQSTM1. Here, we show that the peroxiredoxin-like redox sensor PARK7/DJ-1 modulates the activity of SQSTM1 and the targeting of ubiquitin (Ub)-conjugated proteins to macroautophagy under oxidative stress caused by TNFSF10/TRAIL (tumor necrosis factor [ligand] superfamily, member 10)...
July 6, 2018: Autophagy
Lisa B Frankel
The core macroautophagy/autophagy machinery consists of a large group of autophagy-related (ATG) proteins, that mediate highly controlled, step-wise execution of this conserved intracellular degradation process. Whereas ATG proteins have been intensely studied in terms of protein interactions, post-translational modifications and transcriptional regulation, the mechanisms ensuring efficient translation of ATG proteins are not well understood. In a recent study, we describe an evolutionarily conserved role for EIF5A (eukaryotic translation initiation factor 5A) in autophagy...
July 4, 2018: Autophagy
Xiaoyan Zhang, Yanzhuang Wang
The Golgi apparatus is a central intracellular membrane organelle in the secretory pathway. The formation of the unique stacked architecture of the Golgi ensures accurate protein glycosylation and sorting. However, how the Golgi structure and function respond to extracellular stresses is largely unexplored. In a recent study, we reported that under short-term glucose deprivation, a subpopulation of the Golgi stacking protein GORASP2/GRASP55 is targeted from the Golgi to the interface between autophagosomes and lysosomes to promote autophagosome maturation; this process is regulated by O-GlcNAcylation...
July 4, 2018: Autophagy
Eleanor A Latomanski, Hayley J Newton
Coxiella burnetii is an intracellular bacterial pathogen which causes Q fever, a human infection with the ability to cause chronic disease with potentially life-threatening outcomes. In humans, Coxiella infects alveolar macrophages where it replicates to high numbers in a unique, pathogen-directed lysosome-derived vacuole. This compartment, termed the Coxiella-containing vacuole (CCV), has a low internal pH and contains markers both of lysosomes and autophagosomes. The CCV membrane is also enriched with CLTC (clathrin heavy chain) and this contributes to the success of the CCV...
July 4, 2018: Autophagy
Shin Hye Noh, Heon Yung Gee, Yonjung Kim, He Piao, Jiyoon Kim, Chung Min Kang, Gahyung Lee, Inhee Mook-Jung, Yangsin Lee, Jin Won Cho, Min Goo Lee
The most common mutation in cystic fibrosis patients is a phenylalanine deletion at position 508 (ΔF508) in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. This mutation impairs cell-surface trafficking of CFTR. During cellular stress, core-glycosylated CFTRΔF508 is transported to the cell surface from the endoplasmic reticulum (ER) via an unconventional route that bypasses the Golgi. However, the mechanisms for this unconventional secretory pathway of CFTR are not well delineated. Here, we report that components of the macroautophagy/autophagy and ESCRT (endosomal sorting complex required for transport) pathways are involved in unconventional secretion of CFTR...
July 4, 2018: Autophagy
Chao Yao, Zhongya Ni, Chenyuan Gong, Xiaowen Zhu, Lixin Wang, Zihang Xu, Chunxian Zhou, Suyun Li, Wuxiong Zhou, Chunpu Zou, Shiguo Zhu
Targeting macroautophagy/autophagy is a novel strategy in cancer immunotherapy. In the present study, we showed that the natural product rocaglamide (RocA) enhanced natural killer (NK) cell-mediated lysis of non-small cell lung cancer (NSCLC) cells in vitro and tumor regression in vivo. Moreover, this effect was not related to the NK cell recognition of target cells or expressions of death receptors. Instead, RocA inhibited autophagy and restored the level of NK cell-derived GZMB (granzyme B) in NSCLC cells, therefore increasing their susceptibility to NK cell-mediated killing...
July 4, 2018: Autophagy
Xiaojuan Chao, Hong-Min Ni, Wen-Xing Ding
Macroautophagy/autophagy is a dynamic process, and newly synthesized autophagosomes need to fuse with lysosomes to complete the full process, which is referred to as autophagic degradation or autophagic flux. Therefore, the proper number and function of lysosomes are critical for accomplishing autophagic flux. In a recent study, we found that chronic ethanol consumption impairs TFEB (transcription factor EB) function, which leads to decreased lysosomal biogenesis resulting in hepatic steatosis and liver injury in mice...
July 4, 2018: Autophagy
Yuxin Yin, Guoliang Li, Jingyi Yang, Chunyuan Yang, Minglu Zhu, Yan Jin, Michael A McNutt
PTEN plays an important role in tumor suppression, and PTEN family members are involved in multiple biological processes in various subcellular locations. Here we report that PTENαααthe first identified PTEN isoform, αregulates mitophagy through promotion of PARK2 recruitment to damaged mitochondria. We show that PTENα-deficient mice exhibit accumulation of cardiac mitochondria with structural and functional abnormalities, and PTENα-deficient mouse hearts are more susceptible to injury induced by isoprenaline and ischemia-reperfusion...
July 4, 2018: Autophagy
Annadurai Thangaraj, Palsamy Periyasamy, Ke Liao, Venkata Sunil Bendi, Shannon Callen, Gurudutt Pendyala, Shilpa Buch
While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation...
July 3, 2018: Autophagy
Christian Ungermann, Fulvio Reggiori
Macroautophagy (hereafter autophagy) is a catabolic pathway present in all eukaryotic cells. The yeast Saccharomyces cerevisiae has been pivotal in the identification and characterization of the key autophagy-related (Atg) proteins, which play a central role in the generation of autophagosomes. The components of the core Atg/ATG machinery and their functions are highly conserved among species, although mammalian cells also have isoforms and auxiliary factors. Atg9/ATG9 is the only transmembrane protein that is part of the core Atg/ATG machinery, but it appears to have divergent localizations and molecular roles in yeast and mammals...
July 3, 2018: Autophagy
Weijie Dong, Binfeng He, Hang Qian, Qian Liu, Dong Wang, Jin Li, Zhenghua Wei, Zi Wang, Zhi Xu, Guangyu Wu, Guisheng Qian, Guansong Wang
Microvascular barrier dysfunction is the central pathophysiological feature of acute lung injury (ALI). RAB26 is a newly identified small GTPase involved in the regulation of endothelial cell (EC) permeability. However, the mechanism behind this protection has not been clearly elucidated. Here we found that RAB26 promoted the integrity of adherens junctions (AJs) in a macroautophagy/autophagy-dependent manner in ALI. RAB26 is frequently downregulated in mouse lungs after LPS treatment. Mice lacking Rab26 exhibited phosphorylated SRC expression and increased CDH5/VE-cadherin phosphorylation, leading to AJ destruction...
July 2, 2018: Autophagy
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