BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells.
In conclusion, our study reveals a novel role of BIRC5 in cancer cells as a direct regulator of autophagy. BIRC5 may act as a "bridging molecule", which regulates the interplay between mitosis, apoptosis, and autophagy in embryonic and cancer cells. Abbreviations: ACTA1: actin; ATG: autophagy related; BIRC: baculoviral inhibitor of apoptosis repeat-containing; BAF: bafilomycin A1; CQ: chloroquine; CASP3: caspase 3; HSPB1/Hsp27: heat shock protein family B (small) member 1/heat shock protein 27; IAPs: inhibitors of apoptosis proteins; IP: immunoprecipitation; MAP1LC3/LC3: microtubule associated protein 1 light cha...
Source: Autophagy - October 15, 2019 Category: Cytology Authors: Lin TY, Chan HH, Chen SH, Sarvagalla S, Chen PS, Coumar MS, Cheng SM, Chang YC, Lin CH, Leung E, Cheung CHA Tags: Autophagy Source Type: research

Granulovacuolar degeneration bodies: Red alert for neurons with MAPT/tau pathology.
Abstract In Alzheimer disease patients, MAPT/tau pathology and granulovacuolar degeneration bodies (GVBs) co-occur in the same brain regions and in the same cells. The interdependence of these neuropathological hallmarks and the identity of GVBs have long been elusive. Recently, we showed that MAPT pathology causes GVB formation in neurons in vivo and in vitro. Using these novel GVB models, we identified GVBs as lysosomal structures at the convergence of the endo- and autolysosomal pathways. Here, the possible functional consequences of neuronal GVB formation are discussed. PMID: 31613164 [PubMed - as supplie...
Source: Autophagy - October 15, 2019 Category: Cytology Authors: Wiersma VI, Scheper W Tags: Autophagy Source Type: research

Histone H3F3/H3.3 chaperone DAXX converts to modulate SQSTM1 phase condensation for NFE2L2 activation.
This study suggests a new mechanism of SQSTM1 phase condensation by a protein-protein interaction, and indicates that cytoplasmic DAXX can play a role to regulate redox homeostasis. PMID: 31607206 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - October 14, 2019 Category: Cytology Authors: Yang Y, Valionyte E, Kelly J, Luo S Tags: Autophagy Source Type: research

MCOLN1/TRPML1 inhibition - a novel strategy used by Helicobacter pylori to escape autophagic killing and antibiotic eradication therapy in vivo.
Abstract Inhibition of host macroautophagy/autophagy is one of the strategies used by several intracellular pathogens, including H. pylori, to escape killing. Here we discuss our recent work that revealed the novel mechanism by which the vacuolating cytotoxin A (VacA) produced by H. pylori inhibits lysosomal and autophagic killing. We discovered that VacA impairs the activity of the lysosomal calcium channel MCOLN1/TRPML1 leading to the formation of enlarged, dysfunctional lysosomes and autophagosomes that serve as an intracellular niche, which allows the bacteria to escape eradication therapy. PMID: 31599196...
Source: Autophagy - October 10, 2019 Category: Cytology Authors: Capurro MI, Prashar A, Jones NL Tags: Autophagy Source Type: research

DRD3 (dopamine receptor D3) but not DRD2 activates autophagy through MTORC1 inhibition preserving protein synthesis.
dez T Abstract Growing evidence shows that autophagy is deficient in neurodegenerative and psychiatric diseases, and that its induction may have beneficial effects in these conditions. However, as autophagy shares signaling pathways with cell death and interferes with protein synthesis, prolonged use of autophagy inducers available nowadays is considered unwise. The search for novel autophagy inducers indicates that DRD2 (dopamine receptor 2)-DRD3 ligands may also activate autophagy, though critical aspects of the action mechanisms and effects of dopamine ligands on autophagy are still unknown. In order to shed li...
Source: Autophagy - September 20, 2019 Category: Cytology Authors: Barroso-Chinea P, Luis-Ravelo D, Fumagallo-Reading F, Castro-Hernandez J, Salas-Hernandez J, Rodriguez-Nuñez J, Febles-Casquero A, Cruz-Muros I, Afonso-Oramas D, Abreu-Gonzalez P, Moratalla R, Millan MJ, Gonzalez-Hernandez T Tags: Autophagy Source Type: research

The secret life of degradative lysosomes in axons: delivery from the soma, enzymatic activity, and local autophagic clearance.
Abstract Lysosomal degradation of protein aggregates and damaged organelles is essential for maintaining cellular homeostasis. This process in neurons is challenging due to their highly polarized architecture. While enzymatically active degradative lysosomes are enriched in the cell body, their trafficking and degradation capacity in axons remain elusive. We recently characterized the axonal delivery of degradative lysosomes by applying a set of fluorescent probes that selectively label active forms of lysosomal hydrolases on cortical neurons in microfluidic devices. We revealed that soma-derived degradative lysos...
Source: Autophagy - September 19, 2019 Category: Cytology Authors: Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, Sheng ZH Tags: Autophagy Source Type: research

How bacteria can block xenophagy: an insight from Salmonella.
Abstract Xenophagy, a unique type of selective macroautophagy/autophagy, targets invading pathogens as part of the host immune response. In order to survive within the host, bacteria have established various self-defense mechanisms. In a recent paper from Feng Shao's lab, the Salmonella effector protein SopF has been demonstrated to block xenophagy by interrupting the vacuolar type H+-translocating (v-) ATPase-ATG16L1 axis, which is important for antibacterial autophagy initiation. SopF can specifically ADP-ribosylate Gln124 on ATP6V0C, a v-ATPase component, thus influencing recruitment of ATG16L1 onto the bacteri...
Source: Autophagy - September 18, 2019 Category: Cytology Authors: Wen X, Klionsky DJ Tags: Autophagy Source Type: research

The Paf1 complex transcriptionally regulates the mitochondrial-anchored protein Atg32 leading to activation of mitophagy.
Abstract Mitophagy is a critical process that safeguards mitochondrial quality control in order to maintain proper cellular homeostasis. Although the mitochondrial-anchored receptor Atg32-mediated cargo-recognition system has been well characterized to be essential for this process, the signaling pathway modulating its expression as a contribution of governing the mitophagy process remains largely unknown. Here, bioinformatics analyses of epigenetic or transcriptional regulators modulating gene expression allow us to identify the Paf1 complex (the polymerase-associated factor 1 complex, Paf1C,) as a transcriptiona...
Source: Autophagy - September 16, 2019 Category: Cytology Authors: Zheng L, Shu WJ, Li YM, Mari M, Yan C, Wang D, Yin ZH, Jiang W, Zhou Y, Okamoto K, Reggiori F, Klionsky DJ, Song Z, Du HN Tags: Autophagy Source Type: research

Is WDR45 the missing link for ER stress-induced autophagy in beta-propeller associated neurodegeneration?
Abstract Beta-propeller protein-associated neurodegeneration (BPAN) is caused by mutations in the autophagy gene WDR45/WIPI4. In human, BPAN is associated with static encephalopathy in childhood and neurodegeneration in adulthood (SENDA). It has been proposed that WDR45 mutations cause neurodegeneration due to defective autophagy. Whether these mutations cause a global attenuation or a defect in a subset of autophagy functions is unknown. Based on a recent study showing that wdr45 knockout mice exhibit defective autophagy associated with an increased ER stress, we propose that ER-mediated autophagy, a selective ac...
Source: Autophagy - September 16, 2019 Category: Cytology Authors: Mollereau B, Walter L Tags: Autophagy Source Type: research

A novel role of UBQLNs (ubiquilins) in regulating autophagy, MTOR signaling and v-ATPase function.
Abstract UBQLNs (ubiquilins) are highly conserved proteins across species, characterized by interactions with proteasomes and ubiquitinated proteins via UBA and UBL domains, respectively. The role of UBQLNs as chaperone proteins of the ubiquitin-proteasome system (UPS) is well-defined; however, the connections between UBQLNs and autophagy remain unclear. A recent study published in Nature Cell Biology from Dr. Hugo J. Bellen's lab showed a novel role of UBQLNs in macroautophagy/autophagy regulation through v-ATPase-MTOR signaling using Drosophila and mammalian neuronal cells. Notably, the highlighted article also ...
Source: Autophagy - September 13, 2019 Category: Cytology Authors: Yang Y, Klionsky DJ Tags: Autophagy Source Type: research

De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy.
Abstract Macroautophagy/autophagy can enable cancer cells to withstand cellular stress and maintain bioenergetic homeostasis by sequestering cellular components into newly formed double-membrane vesicles destined for lysosomal degradation, potentially affecting the efficacy of anti-cancer treatments. Using 13C-labeled choline and 13C-magnetic resonance spectroscopy and western blotting, we show increased de novo choline phospholipid (ChoPL) production and activation of PCYT1A (phosphate cytidylyltransferase 1, choline, alpha), the rate-limiting enzyme of phosphatidylcholine (PtdCho) synthesis, during autophagy. We...
Source: Autophagy - September 13, 2019 Category: Cytology Authors: Andrejeva G, Gowan S, Lin G, Wong Te Fong AL, Shamsaei E, Parkes HG, Mui J, Raynaud FI, Asad Y, Vizcay-Barrena G, Nikitorowicz-Buniak J, Valenti M, Howell L, Fleck RA, Martin LA, Kirkin V, Leach MO, Chung YL Tags: Autophagy Source Type: research

Quaternary structures of Vac8 differentially regulate the Cvt and PMN pathways.
Abstract Armadillo (ARM) repeat proteins constitute a large protein family with diverse and fundamental functions in all organisms, and armadillo repeat domains share high structural similarity. However, exactly how these structurally similar proteins can mediate diverse functions remains a long-standing question. Vac8 (vacuole related 8) is a multifunctional protein that plays pivotal roles in various autophagic pathways, including piecemeal microautophagy of the nucleus (PMN) and cytoplasm-to-vacuole targeting (Cvt) pathways in the budding yeast Saccharomyces cerevisiae. Vac8 comprises an H1 helix at the N ...
Source: Autophagy - September 12, 2019 Category: Cytology Authors: Park J, Kim HI, Jeong H, Lee M, Jang SH, Yoon SY, Kim H, Park ZY, Jun Y, Lee C Tags: Autophagy Source Type: research

LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting Mir26a.
This study identified a lncRNA 2810403D21Rik/Mirf that functions as an anti-autophagic molecule via ceRNA activity toward Mir26a. Our findings suggest that knockdown of 2810403D21Rik/Mirf might be a novel therapeutic approach for cardiac diseases associated with autophagy. Abbreviations: 3-MA: 3-methyladenine; AAV-9: adenovirus associated virus-9; agoMir26a: cholesterol-conjugated Mir26a mimic; AMI: acute myocardial infarction; AMO-26a: Mir26a inhibitor; ATG: autophagy related; BECN1: beclin 1; ceRNA: competitive endogenous RNAs; EF: ejection fraction; f-2810403D21Rik/Mirf: fragment encompassing the Mir26a binding site; FS...
Source: Autophagy - September 12, 2019 Category: Cytology Authors: Liang H, Su X, Wu Q, Shan H, Lv L, Yu T, Zhao X, Sun J, Yang R, Zhang L, Yan H, Zhou Y, Li X, Du Z, Shan H Tags: Autophagy Source Type: research

Toward the role of cholesterol and cholesterol transfer protein in autophagosome biogenesis.
Abstract A forward chemical genetic approach led to identification of autogramins as novel autophagy inhibitors. Autogramins selectively target the cholesterol transfer protein GRAMD1A (GRAM domain containing 1A). Autogramins compete with cholesterol binding to the StART domain of GRAMD1A, thereby inhibiting its cholesterol transfer activity. GRAMD1A associates with phosphatidylinositol monophosphate via its GRAM domain. GRAMD1A accumulates at autophagosome initiation sites upon starvation. This protein is involved in cholesterol distribution in response to starvation and is required for autophagosome biogenesis. ...
Source: Autophagy - September 12, 2019 Category: Cytology Authors: Wu YW, Waldmann H Tags: Autophagy Source Type: research

ATG2 regulation of phagophore expansion at mitochondria-associated ER membranes.
Abstract The mechanism by which ATG2 (ATG2A and ATG2B in mammals) regulates autophagosome biogenesis remains largely unknown. In our recent study, we showed that ATG2A translocates to the mitochondria-associated ER membranes (MAM) to promote phagophore growth during nutrient starvation. Mechanistically, the mitochondrial translocase TOMM40 binds to a C-terminal domain of ATG2A, termed the MAM localization domain (MLD), and mediates its MAM translocation in a manner dependent on the TOMM receptor TOMM70. Moreover, ATG2A associates with ATG9A through its N-terminal domain and this interaction is required for phagoph...
Source: Autophagy - September 12, 2019 Category: Cytology Authors: Tang Z, Takahashi Y, Wang HG Tags: Autophagy Source Type: research

SQSTM1-dependent autophagic degradation of PKM2 inhibits the production of mature IL1B/IL-1 β and contributes to LIPUS-mediated anti-inflammatory effect.
SQSTM1-dependent autophagic degradation of PKM2 inhibits the production of mature IL1B/IL-1β and contributes to LIPUS-mediated anti-inflammatory effect. Autophagy. 2019 Sep 10;: Authors: Zhang B, Chen H, Ouyang J, Xie Y, Chen L, Tan Q, Du X, Su N, Ni Z, Chen L Abstract Synovitis is implicated in the pathology of osteoarthritis (OA) and significantly contributes to the development of OA. As a noninvasive physical therapy, low-intensity pulsed ultrasound (LIPUS) has been reported to possess anti-inflammatory effect in recent years. However, the role of LIPUS on synovitis of OA and the underlying me...
Source: Autophagy - September 10, 2019 Category: Cytology Authors: Zhang B, Chen H, Ouyang J, Xie Y, Chen L, Tan Q, Du X, Su N, Ni Z, Chen L Tags: Autophagy Source Type: research

Autophagy Promotes Citrullination of VIM (vimentin) and Its Interaction with Major Histocompatibility Complex class II in Synovial Fibroblasts.
Abstract We aimed to investigate the involvement of macroautophagy/autophagy in autoimmunity in rheumatoid arthritis (RA) through citrullination of VIM (vimentin) and its interaction with MHC class II in synovial fibroblasts (SFs). The cell surface expression of MHC class II and B7 costimulatory molecules on SFs was analyzed by flow cytometry after treatment with IFNG/IFN-γ (interferon gamma). Intracellular citrullinated autoantigens in SFs were analyzed by immunoblotting using serum from anti-citrullinated peptide antibodies (ACPA)-positive patient as a primary antibody. SFs were incubated in serum-free med...
Source: Autophagy - September 5, 2019 Category: Cytology Authors: Sugawara E, Kato M, Kudo Y, Lee W, Hisada R, Fujieda Y, Oku K, Bohgaki T, Amengual O, Yasuda S, Onodera T, Hatakeyama S, Atsumi T Tags: Autophagy Source Type: research

Intracellular crowding by age-dependent neuromelanin accumulation disrupts neuronal proteostasis and triggers Parkinson disease pathology.
Abstract In Parkinson disease (PD), there is a preferential degeneration of neurons that contain the dark-brown cytoplasmic pigment neuromelanin, in particular dopaminergic neurons of the substantia nigra (SN), the loss of which leads to the typical motor symptoms of the disease and constitutes the cardinal pathological diagnostic criterion for PD. Neuromelanin is generally considered a byproduct of dopamine oxidative metabolism and, in humans, it is first detected in early childhood and accumulates progressively with age until occupying most of the neuronal cytoplasm, as neurons apparently lack the means to degra...
Source: Autophagy - September 3, 2019 Category: Cytology Authors: Vila M, Laguna A, Carballo-Carbajal I Tags: Autophagy Source Type: research

The autophagic protein LC3 translocates to the nucleus and localizes in the nucleolus associated to NUFIP1 in response to cyclic mechanical stress.
Abstract The trabecular meshwork (TM) is a key regulatory tissue of intraocular pressure (IOP) in the anterior chamber of eye. Dysfunction of the TM causes resistance to outflow of aqueous humor, which in turn leads to elevated IOP, a main risk factor of glaucomatous neurodegeneration. Due to variations in IOP, TM cells are continuously exposed to mechanical deformations. We previously reported activation of macroautophagy/autophagy, as one of the physiological responses elicited in TM cells following mechanical strain application. By using biochemical fractionation analysis and imaging techniques, we demonstrate ...
Source: Autophagy - September 2, 2019 Category: Cytology Authors: Shim MS, Nettesheim A, Hirt J, Liton PB Tags: Autophagy Source Type: research

New aspects of USP30 biology in the regulation of pexophagy.
te; S Abstract Mitochondria and peroxisomes have a number of features in common: they each play interconnected roles in fatty acid and reactive oxygen species (ROS) metabolism and, once damaged, need to be removed by specialized autophagic mechanisms, termed mitophagy and pexophagy, respectively. Both processes can use ubiquitin as an initiating signal but whereas mitophagy has been extensively studied, pexophagy remains rather poorly understood. Our recent work, along with a new study from Kim and colleagues, has shed light on the molecular mechanism of pexophagy and the importance of reversible ubiquitination in...
Source: Autophagy - July 31, 2019 Category: Cytology Authors: Marcassa E, Kallinos A, Jardine J, Rusilowicz-Jones EV, Clague MJ, Urbé S Tags: Autophagy Source Type: research

Reducing INS-IGF1 signaling protects against non-cell autonomous vesicle rupture caused by SNCA spreading.
This study suggests that the degradation of lysosomal substrates is coordinated across different tissues in metazoan organisms. Because the chronic dissemination of poorly degradable disease proteins into neighboring tissues exerts a non-cell autonomous toxicity, this implies that restoring endo-lysosomal function not only in cells with pathological inclusions, but also in apparently unaffected cell types might help to halt disease progression. Abbreviations: AD: Alzheimer disease; BM: basement membrane; BWM: body wall muscle; CEP: cephalic sensilla; CLEM: correlative light and electron microscopy; CTNS-1: cystinosin (lyso...
Source: Autophagy - July 29, 2019 Category: Cytology Authors: Sandhof CA, Hoppe SO, Druffel-Augustin S, Gallrein C, Kirstein J, Voisine C, Nussbaum-Krammer C Tags: Autophagy Source Type: research

The carboxy-terminus of yeast Atg13 binds phospholipid membrane via motifs that overlap with the Vac8-interacting domain.
Abstract Macroautophagy/autophagy is a conserved catabolic recycling pathway involving the sequestration of cytoplasmic components within double-membrane vesicles termed autophagosomes. The autophagy-related (Atg) protein Atg13 is a key member of the autophagy initiation complex. The Atg13 C terminus is an intrinsically disordered region (IDR) harboring a binding site for the vacuolar membrane protein Vac8. Recent reports suggest Atg13 acts as a hub to assemble the initiation complex, and also participates in membrane recognition. Here we show that the Atg13 C terminus directly binds to lipid membranes via electro...
Source: Autophagy - July 27, 2019 Category: Cytology Authors: Gatica D, Damasio A, Pascual C, Klionsky DJ, Ragusa MJ, Popelka H Tags: Autophagy Source Type: research

Gene essentiality of Tubgcp4: dosage effect and autophagy regulation in retinal photoreceptors.
Abstract Photoreceptor degeneration and damages often lead to blindness, and the underlying molecular mechanisms are largely unknown. There is also a lot of missing information for establishing the role of macroautophagy/autophagy in the retinopathy. We recently generated knockout mouse lines of the essential gene Tubgcp4 (tubulin, gamma complex associated protein 4) and revealed an interplay between essential genes and autophagy regulation. Complete knockout of Tubgcp4 in mice results in early embryonic lethality due to abnormal spindle assembly, whereas heterozygotes are viable through dosage compensation from o...
Source: Autophagy - July 25, 2019 Category: Cytology Authors: Xu X, Shang D, Cheng H, Klionsky DJ, Zhou R Tags: Autophagy Source Type: research

SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy.
Abstract The ubiquitination of mitochondrial proteins labels damaged mitochondria for degradation through mitophagy. We recently developed an in vivo system in which mitophagy is slowed by inhibiting mitochondrial division through knockout of Dnm1l/Drp1, a dynamin related GTPase that mediates mitochondrial division. Using this system, we revealed that the ubiquitination of mitochondrial proteins required SQSTM1/p62, but not the ubiquitin E3 ligase PRKN/parkin, during mitophagy. Here, we tested the role of PINK1, a mitochondrial protein kinase that activates mitophagy by phosphorylating ubiquitin, in mitochondrial ...
Source: Autophagy - July 24, 2019 Category: Cytology Authors: Yamada T, Dawson TM, Yanagawa T, Iijima M, Sesaki H Tags: Autophagy Source Type: research

Suppressing the dark side of autophagy.
Abstract A wide variety of genetic, pharmacological and nutrient manipulations that extend lifespan in model organisms do so in a manner dependent upon increased autophagic flux. However, our recent findings suggest that when mitochondrial membrane integrity is compromised, macroautophagy/autophagy can be detrimental. In C. elegans lacking the serine/threonine kinase mechanistic target of rapamycin kinase complex 2 and its downstream effector SGK-1 (Serum- and Glucocorticoid-inducible Kinase homolog), lifespan is shortened in spite of increased levels of autophagy, whereas reducing autophagy restores normal lifesp...
Source: Autophagy - July 18, 2019 Category: Cytology Authors: Zhou B, Soukas AA Tags: Autophagy Source Type: research

Keeping the autophagy tempo.
Abstract Most essential physiological functions in mammals show a 24-h rhythmic pattern, which includes sleep-wake, feeding-non-feeding cycles and energy metabolism. Recent studies indicate that macroautophagy/autophagy also displays a robust circadian rhythmicity following the daily feeding pattern in adult mammals. We discovered that MiT-TFE transcription factors TFEB and TFE3, master regulators of autophagy and lysosomal biogenesis, are activated in a circadian manner and drive the expression of NR1D1/REV-ERBα, a key component of the core clockwork, thus revealing a molecular link between the nutrient-dri...
Source: Autophagy - July 18, 2019 Category: Cytology Authors: Pastore N, Ballabio A Tags: Autophagy Source Type: research

Autophagy induction by the pathogen receptor NECTIN4 and sustained autophagy contribute to peste des petits ruminants virus infectivity.
Abstract Macroautophagy/autophagy is an essential cellular response in the fight against intracellular pathogens. Although some viruses can escape from or utilize autophagy to ensure their own replication, the responses of autophagy pathways to viral invasion remain poorly documented. Here, we show that peste des petits ruminants virus (PPRV) infection induces successive autophagic signalling in host cells via distinct and uncoupled molecular pathways. Immediately upon invasion, PPRV induced a first transient wave of autophagy via a mechanism involving the cellular pathogen receptor NECTIN4 and an AKT-MTOR-depende...
Source: Autophagy - July 18, 2019 Category: Cytology Authors: Yang B, Xue Q, Guo J, Wang X, Zhang Y, Guo K, Li W, Chen S, Xue T, Qi X, Wang J Tags: Autophagy Source Type: research

Shedding light on autophagy coordinating with cell wall integrity signaling to govern pathogenicity of Magnaporthe oryzae.
Abstract Cells are faced with various stresses during their growth and development, and autophagy is a degradative process in which cells can break down their own components to recycle macromolecules and provide energy under these stresses. For pathogenic fungi that utilize cell wall as the first barrier against external stress, the cell wall integrity (CWI) pathway also provides an essential role in responding to these stresses. However, the specific connection between autophagy and CWI remains elusive in either the model fungi including budding yeast Saccharomyces cerevisiae or the rice blast fungus Magnaporthe ...
Source: Autophagy - July 17, 2019 Category: Cytology Authors: Yin Z, Feng W, Chen C, Xu J, Li Y, Yang L, Wang J, Liu X, Wang W, Gao C, Zhang H, Zheng X, Wang P, Zhang Z Tags: Autophagy Source Type: research

Found art: the yeast vacuole.
Abstract Over the past 9 years I have worked with artists who have used various media to portray the process of autophagy. This has included paintings, protein music, a piano composition, a wood sculpture, a quilt, and a dance. Here, I describe a two-part project that focuses on the vacuole/lysosome. In the initial part of the work I assembled the found-art vacuole; the second part involved the work of a professional watercolor artist, who describes his part of the project from a non-scientist's perspective. PMID: 31305202 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - July 15, 2019 Category: Cytology Authors: Hartley S, Klionsky DJ Tags: Autophagy Source Type: research

A specific ATG-4 isoform is required for autophagic maturation and clearance in C. elegans neurons.
os DA PMID: 31291815 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - July 10, 2019 Category: Cytology Authors: Hill SE, Colón-Ramos DA Tags: Autophagy Source Type: research

New insights into the interplay between autophagy, gut microbiota and inflammatory responses in IBD.
Abstract One of the most significant challenges of inflammatory bowel disease (IBD) research is to understand how alterations in the symbiotic relationship between the genetic composition of the host and the intestinal microbiota, under impact of specific environmental factors, lead to chronic intestinal inflammation. Genome-wide association studies, followed by functional studies, have identified a role for numerous autophagy genes in IBD, especially in Crohn disease. Studies using in vitro and in vivo models, in addition to human clinical studies have revealed that autophagy is pivotal for intestinal homeostasis...
Source: Autophagy - July 9, 2019 Category: Cytology Authors: Larabi A, Barnich N, Nguyen HTT Tags: Autophagy Source Type: research

Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation.
Abstract Impaired macroautophagy/autophagy is involved in the pathogenesis of hepatic fibrosis. However, how aberrant autophagy promotes fibrosis is far from understood. Here, we aimed to define a previously unrevealed pro-fibrotic mechanism for the stress protein TRIB3 (tribbles pseudokinase 3)-mediated autophagy dysfunction. Human fibrotic liver tissues were obtained from patients with cirrhosis who underwent an open surgical repair process. The functional implications of TRIB3 were evaluated in mouse models of hepatic fibrosis induced by bile duct ligation (BDL) or thioacetamide (TAA) injection. Human fibrotic ...
Source: Autophagy - July 9, 2019 Category: Cytology Authors: Zhang XW, Zhou JC, Peng D, Hua F, Li K, Yu JJ, Lv XX, Cui B, Liu SS, Yu JM, Wang F, Jin CC, Yang ZN, Zhao CX, Hou XY, Huang B, Hu ZW Tags: Autophagy Source Type: research

Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis.
tsch U, Saftig P Abstract CTSD (cathepsin D) is one of the major lysosomal proteases indispensable for the maintenance of cellular proteostasis by turning over substrates of endocytosis, phagocytosis and autophagy. Consequently, CTSD deficiency leads to a strong impairment of the lysosomal-autophagy machinery. In mice and humans CTSD dysfunction underlies the congenital variant (CLN10) of neuronal ceroid lipofuscinosis (NCL). NCLs are distinct lysosomal storage disorders (LSDs) sharing various hallmarks, namely accumulation of protein aggregates and ceroid lipofuscin leading to neurodegeneration and blindness. The...
Source: Autophagy - July 8, 2019 Category: Cytology Authors: Marques ARA, Di Spiezio A, Thießen N, Schmidt L, Grötzinger J, Lüllmann-Rauch R, Damme M, Storck SE, Pietrzik CU, Fogh J, Bär J, Mikhaylova M, Glatzel M, Bassal M, Bartsch U, Saftig P Tags: Autophagy Source Type: research

Autophagy links MTOR and GABA signaling in the brain.
Abstract The disruption of MTOR-regulated macroautophagy/autophagy was previously shown to cause autistic-like abnormalities; however, the underlying molecular defects remained largely unresolved. In a recent study, we demonstrated that autophagy deficiency induced by conditional Atg7 deletion in either forebrain GABAergic inhibitory or excitatory neurons leads to a similar set of autistic-like behavioral abnormalities even when induced following the peak period of synaptic pruning during postnatal neurodevelopment. Our proteomic analysis and molecular dissection further revealed a mechanism in which the GABAA rec...
Source: Autophagy - July 7, 2019 Category: Cytology Authors: Hui KK, Tanaka M Tags: Autophagy Source Type: research

Authors: PMID: 31280645 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - July 6, 2019 Category: Cytology Tags: Autophagy Source Type: research

SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed.
Abstract SLC3A2/CD98hc (solute carrier family 3 member 2) and its light chain subunits constitute the heterodimeric transmembrane complexes that mediate amino acid transport and regulate MTOR and macroautophagy/autophagy. Despite the proven tumorigenic role of SLC3A2 in a number of cancers including head and neck squamous cell carcinomas (HNSCC), the link between SLC3A2, autophagy regulation and tumor radioresistance remained elusive. In a recently published study we demonstrated that low levels of SLC3A2 and SLC7A5/LAT1 protein expression significantly correlate with good clinical prognosis in locally advanced HN...
Source: Autophagy - July 5, 2019 Category: Cytology Authors: Digomann D, Linge A, Dubrovska A Tags: Autophagy Source Type: research

Subnanometer resolution cryo-EM structure of Arabidopsis thaliana ATG9.
Abstract Macroautophagy/autophagy is an essential process for the maintenance of cellular homeostasis by recycling macromolecules under normal and stress conditions. ATG9 (autophagy related 9) is the only integral membrane protein in the autophagy core machinery and has a central role in mediating autophagosome formation. In cells, ATG9 exists on mobile vesicles that traffic to the growing phagophore, providing an essential membrane source for the formation of autophagosomes. Here we report the three-dimensional structure of ATG9 from Arabidopsis thaliana at 7.8 Å resolution, determined by single particle cr...
Source: Autophagy - July 5, 2019 Category: Cytology Authors: Lai LTF, Yu C, Wong JSK, Lo HS, Benlekbir S, Jiang L, Lau WCY Tags: Autophagy Source Type: research

CALCOCO2/NDP52 initiates selective autophagy through recruitment of ULK and TBK1 kinase complexes.
Abstract The selective macroautophagy of prospective cargo necessitates activity of the autophagy machinery at cargo-determined locations. Whether phagophore membranes are recruited to, or are generated de novo at, the cargo is unknown. In our recent study we show that damaged Salmonella-containing vacuoles, marked by LGALS8/galectin-8, engage the cargo receptor CALCOCO2/NDP52 to recruit the autophagy-initiating ULK and TBK1 complexes and cause the formation of WIPI2-positive phagophore membranes. CALCOCO2 functions in the induction of autophagy by forming a trimer with RB1CC1/FIP200 and TBKBP1/SINTBAD-AZI2/NAP1, ...
Source: Autophagy - July 1, 2019 Category: Cytology Authors: Boyle KB, Ravenhill BJ, Randow F Tags: Autophagy Source Type: research

Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney stone development.
Abstract Kidney stone disease is a lifestyle-related disease prevalent in developed countries; however, effective medical treatment for the disease is not yet well established. As cellular damage in renal tubular cells (RTCs) is responsible for the disease, here, we focused on the role of macroautophagy/autophagy in RTCs. We found that autophagic activity was significantly decreased in mouse RTCs exposed to calcium oxalate (CaOx) monohydrate crystals and in the kidneys of GFP-conjugated MAP1LC3B (microtubule- associated protein 1 light chain 3 beta) transgenic mice with CaOx nephrocalcinosis induced by glyoxyla...
Source: Autophagy - June 29, 2019 Category: Cytology Authors: Unno R, Kawabata T, Taguchi K, Sugino T, Hamamoto S, Ando R, Okada A, Kohri K, Yoshimori T, Yasui T Tags: Autophagy Source Type: research

4,4'-Dimethoxychalcone: a natural flavonoid that promotes health through autophagy-dependent and -independent effects.
Abstract The age-induced deterioration of the organism results in detrimental and ultimately lethal pathologies. The process of aging itself involves a plethora of different mechanisms that should be subverted concurrently to delay and/or prevent age-related maladies. We have identified a natural compound, 4,4'-dimethoxychalcone (DMC), which promotes longevity in yeast, worms and flies, and protects mice from heart injury and liver toxicity. Interestingly, both the DMC-mediated lifespan extension and the cardioprotection depend on macroautophagy/autophagy whereas hepatoprotection does not. DMC induces autophagy by...
Source: Autophagy - June 28, 2019 Category: Cytology Authors: Zimmermann A, Kainz K, Hofer SJ, Bauer MA, Schroeder S, Dengjel J, Pietrocola F, Kepp O, Ruckenstuhl C, Eisenberg T, Sigrist SJ, Madeo F, Carmona-Gutierrez D, Kroemer G Tags: Autophagy Source Type: research

NIPSNAP1 and NIPSNAP2 act as "eat me" signals to allow sustained recruitment of autophagy receptors during mitophagy.
NIPSNAP1 and NIPSNAP2 act as "eat me" signals to allow sustained recruitment of autophagy receptors during mitophagy. Autophagy. 2019 Jun 28;: Authors: Abudu YP, Pankiv S, Mathai BJ, Lamark T, Johansen T, Simonsen A Abstract Removal of damaged mitochondria is vital for cellular homeostasis especially in non-dividing cells, like neurons. Damaged mitochondria that cannot be repaired by the ubiquitin-proteasomal system are cleared by a form of selective autophagy known as mitophagy. Following damage, mitochondria become labelled with "eat-me" signals that selectively determine their d...
Source: Autophagy - June 28, 2019 Category: Cytology Authors: Abudu YP, Pankiv S, Mathai BJ, Lamark T, Johansen T, Simonsen A Tags: Autophagy Source Type: research

DIPK2A Promotes STX17- and VAMP7-mediated Autophagosome-lysosome Fusion by Binding to VAMP7B.
Abstract Autophagosome and lysosome fusion is an important macroautophagy/autophagy process for cargo degradation, and SNARE proteins, including STX17, SNAP29, VAMP7 and VAMP8, are key players in this process. However, the manner in which this process is precisely regulated is poorly understood. Here, we show that VAMP7B, a SNARE domain-disrupted isoform of R-SNARE protein VAMP7, competes with SNARE domain functional isoform VAMP7A to bind to STX17 and inhibits autophagosome-lysosome fusion. Moreover, we show that DIPK2A, a late endosome- and lysosome-localized protein, binds to VAMP7B, which inhibits the interact...
Source: Autophagy - June 28, 2019 Category: Cytology Authors: Tian X, Zheng P, Zhou C, Wang X, Ma H, Ma W, Zhou X, Teng J, Chen J Tags: Autophagy Source Type: research

The ubiquitin-specific protease USP8 directly deubiquitinates SQSTM1/p62 to suppress its autophagic activity.
Abstract SQSTM1/p62 (sequestosome 1) is a critical macroautophagy/autophagy receptor that promotes the formation and degradation of ubiquitinated aggregates. SQSTM1 can be modified by ubiquitination, and this modification modulates its autophagic activity. However, the molecular mechanisms underpinning its reversible deubiquitination have never been described. Here we report that USP8 (ubiquitin specific peptidase 8) directly interacted with and deubiquitinated SQSTM1. USP8 preferentially removed the lysine 11 (K11)-linked ubiquitin chains from SQSTM1. Moreover, USP8 deubiquitinated SQSTM1 principally at K420 with...
Source: Autophagy - June 26, 2019 Category: Cytology Authors: Peng H, Yang F, Hu Q, Sun J, Peng C, Zhao Y, Huang C Tags: Autophagy Source Type: research

Revisiting the role of autophagy in melanoma.
Abstract Although alterations of the macroautophagy/autophagy-lysosome pathway have been observed in cancer for many years, the mechanisms underlying these changes and the importance of autophagic and lysosomal reprogramming by cancer have yet to be well identified. Our recent study demonstrates that oncogenic BRAF signaling promotes melanoma growth and resistance to BRAF-targeted therapy through phosphorylation and functional inactivation of TFEB (transcription factor EB) and consequent suppression of the autophagy-lysosome gene network. This is by no means the first time that this pathway has been directly linke...
Source: Autophagy - June 26, 2019 Category: Cytology Authors: Li S, Song Y, Quach C, Nemecio D, Liang C Tags: Autophagy Source Type: research

Upregulation of ATG7 Attenuates Motor Neuron Dysfunction Associated with Depletion of TARDBP/TDP-43.
Abstract A shared neuropathological hallmark in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is nuclear clearance and cytoplasmic aggregation of TARDBP/TDP-43 (TAR DNA binding protein). We previously showed that the ability of TARDBP to repress nonconserved cryptic exons was impaired in brains of patients with ALS and FTD, suggesting that its nuclear depletion contributes to neurodegeneration. However, the critical pathways impacted by the failure to repress cryptic exons that may contribute to neurodegeneration remain undefined. Here, we report that transcriptome analysis of TARDBP-defici...
Source: Autophagy - June 26, 2019 Category: Cytology Authors: Donde A, Sun M, Jeong YH, Wen X, Ling J, Lin S, Braunstein K, Nie S, Wang S, Chen L, Wong PC Tags: Autophagy Source Type: research

MIR145-3p promotes autophagy and enhances bortezomib sensitivity in multiple myeloma by targeting HDAC4.
In this study, we investigated the role of MIR145-3p (microRNA 145-3p) in MM, with focus on cellular processes autophagy and cell death. Our results provided evidence that downregulation of MIR145-3p expression was associated with disease progression in human MM. MIR145-3p triggered autophagic flux through direct targeting of HDAC4 (histone deacetylase 4) in MM cells, leading to enhanced apoptosis. Silencing HDAC4 recapitulated the effects of MIR145-3p, whereas enforced expression of HDAC4 abrogated the effects of MIR145-3p. Furthermore, we showed that suppression of HDAC4 by MIR145-3p resulted in upregulation of the pro-a...
Source: Autophagy - June 26, 2019 Category: Cytology Authors: Wu H, Liu C, Yang Q, Xin C, Du J, Sun F, Zhou L Tags: Autophagy Source Type: research

A TRIM32-AMBRA1-ULK1 complex initiates the autophagy response in atrophic muscle cells.
In conclusion, we have identified a novel molecular mechanism by which autophagy is regulated in muscles, whose alteration is associated with the development of muscular dystrophy. PMID: 31234693 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - June 25, 2019 Category: Cytology Authors: Di Rienzo M, Piacentini M, Fimia GM Tags: Autophagy Source Type: research

Topology-dependent, bifurcated mitochondrial quality control under starvation.
This study reveals a novel morphological selection for control of mitochondrial quality and quantity under starvation. PMID: 31234709 [PubMed - as supplied by publisher] (Source: Autophagy)
Source: Autophagy - June 25, 2019 Category: Cytology Authors: Zhou Y, Long Q, Wu H, Li W, Qi J, Wu Y, Xiang G, Tang H, Yang L, Chen K, Li L, Bao F, Li H, Wang Y, Li M, Liu X Tags: Autophagy Source Type: research

Autophagy, Inflammation, and Metabolism (AIM) Center in its second year.
G, Kimchi A, Ktistakis N, Kroemer G, Mizushima N, Münz C, Reggiori F, Rubinsztein D, Ryan K, Schroder K, Shen HM, Simonsen A, Tooze SA, Vaccaro M, Yoshimori T, Yu L, Zhang H, Klionsky DJ Abstract The NIH-funded center for autophagy research named Autophagy, Inflammation, and Metabolism (AIM) Center of Biomedical Research Excellence, located at the University of New Mexico Health Science Center is now completing its second year as a working center with a mission to promote autophagy research locally, nationally, and internationally. The center has thus far supported a cadre of 6 junior faculty (mentored PIs; ...
Source: Autophagy - June 25, 2019 Category: Cytology Authors: Deretic V, Prossnitz E, Burge M, Campen MJ, Cannon J, Liu KJ, Hall P, Sklar LA, Allers L, Mariscal L, Garcia SA, Baehrecke EH, Behrends C, Cecconi F, Codogno P, Chen GC, Elazar Z, Eskelinen EL, Fourie B, Gozuacik D, Hong W, Jo EK, Johansen T, Juhász G, K Tags: Autophagy Source Type: research

PLA2G4A/cPLA2-mediated lysosomal membrane damage leads to inhibition of autophagy and neurodegeneration after brain trauma.
Abstract Lysosomal membrane permeabilization (LMP) is observed under many pathological conditions, leading to cellular dysfunction and death. However, the mechanisms by which lysosomal membranes become leaky in vivo are not clear. Our data demonstrate that LMP occurs in neurons following controlled cortical impact induced (CCI) traumatic brain injury (TBI) in mice, leading to impaired macroautophagy (autophagy) and neuronal cell death. Comparison of LC-MS/MS lysosomal membrane lipid profiles from TBI and sham animals suggested a role for PLA2G4A/cPLA2 (phospholipase A2, group IVA [cytosolic, calcium-dependent]) in...
Source: Autophagy - June 25, 2019 Category: Cytology Authors: Sarkar C, Jones JW, Hegdekar N, Thayer JA, Kumar A, Faden AI, Kane MA, Lipinski MM Tags: Autophagy Source Type: research