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Autophagy

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https://www.readbyqxmd.com/read/28085563/the-e3-ubiquitin-ligase-nedd4-is-an-lc3-interactive-protein-and-regulates-autophagy
#1
Aiqin Sun, Jing Wei, Chandra Childress, John H Shaw Iv, Ke Peng, Genbao Shao, Wannian Yang, Qiong Lin
The MAP1LC3/LC3 family plays an essential role in autophagosomal biogenesis and transport. In this report, we show that the HECT family E3 ubiquitin ligase NEDD4 interacts with LC3 and is involved in autophagosomal biogenesis. NEDD4 binds to LC3 through a conserved WXXL LC3-binding motif in a region between the C2 and the WW2 domains. Knockdown of NEDD4 impaired starvation- or rapamycin-induced activation of autophagy and autophagosomal biogenesis and caused aggregates of the LC3 puncta colocalized with endoplasmic reticulum membrane markers...
January 13, 2017: Autophagy
https://www.readbyqxmd.com/read/28085543/deletion-of-prkaa-triggers-mitochondrial-fission-by-inhibiting-the-autophagy-dependent-degradation-of-dnm1l
#2
Qilong Wang, Shengnan Wu, Huaiping Zhu, Ye Ding, Xiaoyan Dai, Changhan Ouyang, Young-Min Han, Zhonglin Xie, Ming-Hui Zou
PRKAA (protein kinase, AMP-activated, α catalytic subunit) regulates mitochondrial biogenesis, function, and turnover. However, the molecular mechanisms by which PRKAA regulates mitochondrial dynamics remain poorly characterized. Here, we report that PRKAA regulated mitochondrial fission via the autophagy-dependent degradation of DNM1L (dynamin 1-like). Deletion of Prkaa1/AMPKα1 or Prkaa2/AMPKα2 resulted in defective autophagy, DNM1L accumulation, and aberrant mitochondrial fragmentation in the mouse aortic endothelium...
January 13, 2017: Autophagy
https://www.readbyqxmd.com/read/28059666/mtorc1-mediated-nrbf2-phosphorylation-functions-as-a-switch-for-the-class-iii-ptdins3k-and-autophagy
#3
Xi Ma, Shen Zhang, Long He, Yueguang Rong, Livia Wilz Brier, Qiming Sun, Rong Liu, Weiliang Fan, She Chen, Zhenyu Yue, Joungmok Kim, Kun-Liang Guan, Defa Li, Qing Zhong
NRBF2/Atg38 has been identified as the fifth subunit of the macroautophagic/autophagic class III phosphatidylinositol 3-kinase (PtdIns3K) complex, along with ATG14/Barkor, BECN1/Vps30, PIK3R4/p150/Vps15 and PIK3C3/Vps34. However, its functional mechanism and regulation are not fully understood. Here, we report that NRBF2 is a fine tuning regulator of PtdIns3K controlled by phosphorylation. Human NRBF2 is phosphorylated by MTORC1 at S113 and S120. Upon nutrient starvation or MTORC1 inhibition, NRBF2 phosphorylation is diminished...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28059587/metabolic-effects-of-fasting-on-human-and-mouse-blood-in-vivo
#4
Federico Pietrocola, Yohann Demont, Francesca Castoldi, David Enot, Sylvère Durand, Michaela Semeraro, Elisa Elena Baracco, Jonathan Pol, Jose Manuel Bravo-San Pedro, Chloé Bordenave, Sarah Levesque, Juliette Humeau, Alexis Chery, Didier Métivier, Frank Madeo, M Chiara Maiuri, Guido Kroemer
Starvation is a strong physiological stimulus of macroautophagy/autophagy. In this study, we addressed the question as to whether it would be possible to measure autophagy in blood cells after nutrient deprivation. Fasting of mice for 48 h (which causes ∼20% weight loss) or starvation of human volunteers for up to 4 days (which causes <2% weight loss) provokes major changes in the plasma metabolome, yet induces only relatively minor alterations in the intracellular metabolome of circulating leukocytes...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28059583/mir7-3hg-a-myc-dependent-modulator-of-cell-proliferation-inhibits-autophagy-by-a-regulatory-loop-involving-ambra1
#5
Mariacristina Capizzi, Flavie Strappazzon, Valentina Cianfanelli, Elena Papaleo, Francesco Cecconi
Macroautophagy/autophagy is a tightly regulated intracellular catabolic pathway involving the lysosomal degradation of cytoplasmic organelles and proteins to be recycled into metabolic precursors. AMBRA1 (autophagy and beclin 1 regulator 1) has a central role in the autophagy signaling network; it acts upstream of MTORC1-dependent autophagy by stabilizing the kinase ULK1 (unc-51 like autophagy activating kinase 1) and by favoring autophagosome core complex formation. AMBRA1 also regulates the cell cycle by modulating the activity of the phosphatase PPP2/PP2A (protein phosphatase 2) and degradation of MYC...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28059582/prkcd-pkc%C3%AE-contributes-to-nephrotoxicity-during-cisplatin-chemotherapy-by-suppressing-autophagy
#6
Dongshan Zhang, Xuan Xu, Zheng Dong
Nephrotoxicity is a major side effect during chemotherapy with cisplatin and related platinum compounds. Previous work unveiled a role of PRKCD/PKCδ (protein kinase C delta) in cisplatin-induced nephrotoxicity; however, the underlying mechanism was largely unknown. Our recent work showed that PRKCD may suppress macroautophagy/autophagy, a cytoprotective mechanism, to promote kidney tubule cell death during cisplatin treatment. Interestingly, PRKCD may do so by phosphorylating AKT, which further phosphorylates MTOR to repress ULK1...
January 6, 2017: Autophagy
https://www.readbyqxmd.com/read/28056186/tampering-with-cancer-chemoresistance-by-targeting-the-tgm2-il6-autophagy-regulatory-network
#7
Han Zhang, Nami McCarty
Macroautophagy/autophagy is a well-established process involved in maintaining cellular homeostasis, but its role in cancer is complex and even controversial. Many studies have reported a correlative relationship between increased autophagy and evolving cancer cells under stress conditions such as nutrient or oxygen deprivation; however, there has been a lack of a plausible mechanistic link to properly target the autophagy process in the context of this microenvironment. We recently unveiled a positive regulatory loop involving TGM2 (transglutaminase 2)-NFKB/NF-κB signaling, IL6 and autophagy in cancer using mantle cell lymphoma (MCL) as a model system...
January 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28055310/gastrointestinal-stromal-tumors-gist-facing-cell-death-between-autophagy-and-apoptosis
#8
Gloria Ravegnini, Giulia Sammarini, Margherita Nannini, Maria A Pantaleo, Guido Biasco, Patrizia Hrelia, Sabrina Angelini
Autophagy and apoptosis are 2 fundamental biological mechanisms that may cooperate or be antagonistic, although both are involved in deciding the fate of cells in physiological or pathological conditions. These 2 mechanisms coexist simultaneously in cells and share common upstream signals and stimuli. Autophagy and apoptosis play pivotal roles in cancer development. Autophagy plays a key function in maintaining tumor cell survival by providing energy during unfavorable metabolic conditions through its recycling mechanism, and supporting the high energy requirement for metabolism and growth...
January 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28055301/autophagy-orchestrates-adaptive-responses-to-targeted-therapy-in-endometrial-cancer
#9
Núria Eritja, Bo-Juen Chen, Ruth Rodríguez-Barrueco, Maria Santacana, Sònia Gatius, August Vidal, Maria Dolores Martí, Jordi Ponce, Laura Bergadà, Andree Yeramian, Mario Encinas, Joan Ribera, Jaume Reventós, Jeff Boyd, Alberto Villanueva, Xavier Matias-Guiu, Xavier Dolcet, David Llobet-Navàs
Targeted therapies in endometrial cancer (EC) using kinase inhibitors rarely result in complete tumor remission and are frequently challenged by the appearance of refractory cell clones, eventually resulting in disease relapse. Dissecting adaptive mechanisms is of vital importance to circumvent clinical drug resistance and improve the efficacy of targeted agents in EC. Sorafenib is an FDA-approved multitarget tyrosine and serine/threonine kinase inhibitor currently used to treat hepatocellular carcinoma, advanced renal carcinoma and radioactive iodine-resistant thyroid carcinoma...
January 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28055300/multistep-regulation-of-tfeb-by-mtorc1
#10
Silvia Vega-Rubin-de-Celis, Samuel Peña-Llopis, Meghan Konda, James Brugarolas
The master regulator of lysosome biogenesis, TFEB, is regulated by MTORC1 through phosphorylation at S211, and the S211A mutation increases nuclear localization. However, TFEB(S211A) localizes diffusely in both cytoplasm and nucleus and, as we show, retains regulation by MTORC1. Here, we report that endogenous TFEB is phosphorylated at S122 in an MTORC1-dependent manner, that S122 is phosphorylated in vitro by recombinant MTOR, and that S122 is important for TFEB regulation by MTORC1. Specifically, nuclear localization following MTORC1 inhibition is blocked by a S122D mutation (despite S211 dephosphorylation)...
January 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28055290/heme-and-iron-induce-protein-aggregation
#11
Leonardo H Travassos, Luiz R C Vasconcellos, Marcelo T Bozza, Leticia A M Carneiro
No abstract text is available yet for this article.
January 5, 2017: Autophagy
https://www.readbyqxmd.com/read/28045574/autophagy-and-krt8-keratin-8-protect-degeneration-of-retinal-pigment-epithelium-under-oxidative-stress
#12
Ahruem Baek, Soojin Yoon, Jean Kim, Yu Mi Baek, Hanna Park, Daehan Lim, Hyewon Chung, Dong-Eun Kim
Contribution of autophagy and regulation of related proteins to the degeneration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD) remain unknown. We report that upregulation of KRT8 (keratin 8) as well as its phosphorylation are accompanied with autophagy and attenuated with the inhibition of autophagy in RPE cells under oxidative stress. KRT8 appears to have a dual role in RPE pathophysiology. While increased expression of KRT8 following autophagy provides a cytoprotective role in RPE, phosphorylation of KRT8 induces pathologic epithelial-mesenchymal transition (EMT) of RPE cells under oxidative stress, which is mediated by MAPK1/ERK2 (mitogen-activated protein kinase 1) and MAPK3/ERK1...
January 3, 2017: Autophagy
https://www.readbyqxmd.com/read/28026986/xenophagy-a-battlefield-between-host-and-microbe-and-a-possible-avenue-for-cancer-treatment
#13
Kai Mao, Daniel J Klionsky
In eukaryotes, xenophagy is defined as a type of selective macroautophagy/autophagy that is used for eliminating invading pathogens. In contrast to other types of selective autophagy, such as mitophagy, pexophagy and ribophagy, xenophagy is used by eukaryotes for targeting microbes-hence the prefix "xeno" meaning "other" or "foreign"-that have infected a host cell, leading to their lysosomal degradation. This unique characteristic links xenophagy to antibacterial and antiviral defenses, as well as the immune response...
December 27, 2016: Autophagy
https://www.readbyqxmd.com/read/28026976/spermidine-boosts-autophagy-to-protect-from-synapse-aging
#14
Anuradha Bhukel, Frank Madeo, Stephan Sigrist
All animals form memories to adapt their behavior in a context-dependent manner. With increasing age, however, forming new memories becomes less efficient. While synaptic plasticity promotes memory formation, the etiology of age-induced memory formation remained enigmatic. Previous work showed that simple feeding of polyamine spermidine protects from age-induced memory impairment in Drosophila. Most recent work now shows that spermidine operates directly at synapses, allowing for an autophagy-dependent homeostatic regulation of presynaptic specializations...
December 27, 2016: Autophagy
https://www.readbyqxmd.com/read/28026975/the-notch1-autophagy-interaction-regulating-self-eating-for-survival
#15
Apurva Sarin, Nimi Marcel
T-cell subsets in the mammalian immune system use varied mechanisms for survival, a demand imposed by the diverse and dynamic niches that they function in. In a recent study, we showed that survival of natural T-regulatory cells (Tregs) was determined by spatially regulated NOTCH1 activity signaling leading to the activation of macroautophagy/autophagy. While this interaction was revealed in experimental conditions of limited nutrient availability in vitro, the consequences of this interaction were confirmed in the context of immune physiology...
December 27, 2016: Autophagy
https://www.readbyqxmd.com/read/27977328/transcriptional-regulation-of-core-autophagy-and-lysosomal-genes-by-the-androgen-receptor-promotes-prostate-cancer-progression
#16
Alicia M Blessing, Kimal Rajapakshe, Lakshmi Reddy Bollu, Yan Shi, Mark A White, Alexander H Pham, Chenchu Lin, Philip Jonsson, Constanza J Cortes, Edwin Cheung, Albert R La Spada, Robert C Bast, Fatima A Merchant, Cristian Coarfa, Daniel E Frigo
AR (androgen receptor) signaling is crucial for the development and maintenance of the prostate as well as the initiation and progression of prostate cancer. Despite the AR's central role in prostate cancer progression, it is still unclear which AR-mediated processes drive the disease. Here, we identified 4 core autophagy genes: ATG4B, ATG4D, ULK1, and ULK2, in addition to the transcription factor TFEB, a master regulator of lysosomal biogenesis and function, as transcriptional targets of AR in prostate cancer...
December 15, 2016: Autophagy
https://www.readbyqxmd.com/read/27929731/autophagic-homeostasis-is-required-for-the-pluripotency-of-cancer-stem-cells
#17
Tanveer Sharif, Emma Martell, Cathleen Dai, Barry E Kennedy, Patrick Murphy, Derek R Clements, Youra Kim, Patrick W K Lee, Shashi A Gujar
Pluripotency is an important feature of cancer stem cells (CSCs) that contributes to self-renewal and chemoresistance. The maintenance of pluripotency of CSCs under various pathophysiological conditions requires a complex interaction between various cellular pathways including those involved in homeostasis and energy metabolism. However, the exact mechanisms that maintain the CSC pluripotency remain poorly understood. In this report, using both human and murine models of CSCs, we demonstrate that basal levels of autophagy are required to maintain the pluripotency of CSCs, and that this process is differentially regulated by the rate-limiting enzyme in the NAD(+) synthesis pathway NAMPT (nicotinamide phosphoribosyltransferase) and the transcription factor POU5F1/OCT4 (POU class 5 homeobox 1)...
December 8, 2016: Autophagy
https://www.readbyqxmd.com/read/27929729/fyco1-and-autophagy-control-the-integrity-of-the-haploid-male-germ-cell-specific-rnp-granules
#18
Matteo Da Ros, Tiina Lehtiniemi, Opeyemi Olotu, Daniel Fischer, Fu-Ping Zhang, Helena Vihinen, Eija Jokitalo, Anu Sironen, Jorma Toppari, Noora Kotaja
Ribonucleoprotein (RNP) granules play a major role in compartmentalizing cytoplasmic RNA regulation. Haploid round spermatids that have exceptionally diverse transcriptomes are characterized by a unique germ cell-specific RNP granule, the chromatoid body (CB). The CB shares many characteristics with somatic RNP granules but also has germline-specific features. The CB appears to be a central structure in PIWI-interacting RNA (piRNA)-targeted RNA regulation. Here, we identified a novel CB component, FYCO1, which is involved in the intracellular transport of autophagic vesicles in somatic cells...
December 8, 2016: Autophagy
https://www.readbyqxmd.com/read/27929719/nad-the-convergence-of-dna-repair-and-mitophagy
#19
Evandro F Fang, Vilhelm A Bohr
ATM is a 350 kDa serine/threonine kinase best known for its role in DNA repair and multiple cellular homeostasis pathways. Mutation in ATM causes the disease ataxia telangiectasia (A-T) with clinical features including ataxia, severe cerebellar atrophy and Purkinje cell loss. In a cross-species study, using primary rat neurons, the roundworm C. elegans, and a mouse model of A-T, we showed that loss of ATM induces mitochondrial dysfunction and compromised mitophagy due to NAD(+) insufficiency. Remarkably, NAD(+) repletion mitigates both the DNA repair defect and mitochondrial dysfunction in ATM-deficient neurons...
December 8, 2016: Autophagy
https://www.readbyqxmd.com/read/27929705/snapin-is-critical-for-lysosomal-acidification-and-autophagosome-maturation-in-macrophages
#20
Bo Shi, Qi-Quan Huang, Robert Birkett, Renee Doyle, Andrea Dorfleutner, Christian Stehlik, Congcong He, Richard M Pope
We previously observed that SNAPIN, which is an adaptor protein in the SNARE core complex, was highly expressed in rheumatoid arthritis synovial tissue macrophages, but its role in macrophages and autoimmunity is unknown. To identify SNAPIN's role in these cells, we employed siRNA to silence the expression of SNAPIN in primary human macrophages. Silencing SNAPIN resulted in swollen lysosomes with impaired CTSD (cathepsin D) activation, although total CTSD was not reduced. Neither endosome cargo delivery nor lysosomal fusion with endosomes or autophagosomes was inhibited following the forced silencing of SNAPIN...
December 8, 2016: Autophagy
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