Mechanisms and Functions of Pexophagy in Mammalian Cells
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Peroxisome: the New Player in Ferroptosis
Signal Transduction and Targeted Therapy www.nature.com/sigtrans RESEARCH HIGHLIGHT OPEN Peroxisome: the new player in ferroptosis Daolin Tang1,2 and Guido Kroemer 3,4,5 Signal Transduction and Targeted Therapy (2020) 5:273; https://doi.org/10.1038/s41392-020-00404-3 A recent paper published in Nature by Zou et al. reported that peroxisomes was positively correlated with susceptibility to peroxisomes, membrane-bound oxidative organelles, contribute ferroptosis. Therefore, peroxisomes may be added to the list of to ferroptosis through the biosynthesis of plasmalogens for lipid organelles that can initiate the ferroptotic cell death.5 peroxidation (Fig. 1).1 These observations provide new insights Subsequently, the author explored how peroxisomes affect the into the lipid metabolic basis of ferroptotic cell death. sensitivity of cells to ferroptosis. Peroxisomal enzymes involved in Cell death, which is essential for organismal homeostasis, the synthesis of plasmalogens, such as alkylglycerone phosphate exhibits multiple subroutines with different molecular mechan- synthase (AGPS), fatty acyl-CoA reductase 1 (FAR1), and glycer- isms and signaling cascades.2 Within the expanding typology of onephosphate O-acyltransferase (GNPAT), were significantly regulated cell death pathways, ferroptosis is an iron-dependent enriched among the CRISPR targets that confer cytoprotection. non-apoptotic cell death caused by unrestrained lipid peroxida- Lipidomic analysis revealed that the production of plasmalogens tion culminating in irreversible plasma membrane -
PEX2 Is the E3 Ubiquitin Ligase Required for Pexophagy During Starvation
JCB: Article PEX2 is the E3 ubiquitin ligase required for pexophagy during starvation Graeme Sargent,1,6 Tim van Zutphen,7 Tatiana Shatseva,6 Ling Zhang,3 Valeria Di Giovanni,3 Robert Bandsma,2,3,4,5 and Peter Kijun Kim1,6 1Cell Biology Department, 2Department of Paediatric Laboratory Medicine, 3Physiology and Experimental Medicine Program, Research Institute, 4Division of Gastroenterology, Hepatology and Nutrition, and 5Centre for Global Child Health, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada 6Biochemistry Department, University of Toronto, Toronto, ON M5S 1A8, Canada 7Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, 9700 AD Groningen, Netherlands Peroxisomes are metabolic organelles necessary for anabolic and catabolic lipid reactions whose numbers are highly dynamic based on the metabolic need of the cells. One mechanism to regulate peroxisome numbers is through an auto- phagic process called pexophagy. In mammalian cells, ubiquitination of peroxisomal membrane proteins signals pexo- phagy; however, the E3 ligase responsible for mediating ubiquitination is not known. Here, we report that the peroxisomal E3 ubiquitin ligase peroxin 2 (PEX2) is the causative agent for mammalian pexophagy. Expression of PEX2 leads to Downloaded from gross ubiquitination of peroxisomes and degradation of peroxisomes in an NBR1-dependent autophagic process. We identify PEX5 and PMP70 as substrates of PEX2 that are ubiquitinated during amino acid starvation. We also find that PEX2 expression is up-regulated during both amino acid starvation and rapamycin treatment, suggesting that the mTORC1 pathway regulates pexophagy by regulating PEX2 expression levels. Finally, we validate our findings in vivo using an animal model. -
Autophagy Controls Centrosome Number
www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 9), pp: 14277-14278 Editorial: Autophagy and Cell Death Autophagy controls centrosome number Shinya Honda and Shigeomi Shimizu It is believed that the number of centrosomes in a that in normal cells, and (4) silencing Cep63 decreased cell is tightly regulated by the degradation of centrosomal the number of centrosomes in autophagy-deficient cells. proteins via the ubiquitin–proteasome protein degradation From these findings, we concluded that Cep63 dots are the system. However, we recently demonstrated that direct substrates of autophagy and multiple centrosomes autophagy also participates in the regulation of centrosome are generated from the excess Cep63 dots in autophagy- number. deficient cells. The centrosome is the major component of the Consistent with these findings, in autophagy- microtubule organizing center of mammalian cells, deficient cells, most Cep63 dots directly bound to p62, and plays an essential role in chromosome segregation an adaptor or cargo receptor for autophagic degradation. during cell division. Centrosome number is tightly These p62-associated Cep63 dots were not become mature regulated during the cell cycle: G1 cells have one mature centrosomes, whereas some Cep63 dots become mature centrosome containing a pair of centrioles. Centriole centrosomes by their interaction with Cep152, instead of replication occurs during the S phase, and each centriole p62. Cep152 is the first protein to interact with Cep63 in duplicates to produce two daughter centrioles, to generate the initial step of centriole duplication (Figure 1). two centrosomes in the G2–M phase. If cells have more Our data indicated that Cep63 dots are continuously than three centrosomes during metaphase, this causes generated and rapidly degraded by autophagy. -
Autophagy Regulation by RNA Decay
On the edge of degradation: Autophagy regulation by RNA decay Elizabeth Delorme-Axford1 and Daniel J. Klionsky1# From the 1Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA # Correspondence to: Daniel J. Klionsky; University of Michigan; Life Sciences Institute; Rm. 6036; 210 Washtenaw Ave.; Ann Arbor, Michigan 48109-2216 USA; Email: [email protected] Keywords: Dcp2, DDX6, Dhh1, mRNA decay, RNA degradation, vacuole, Xrn1/XRN1, yeast Abbreviations: ATG, autophagy-related; CPA, cleavage and polyadenylation; Cvt, cytoplasm- to-vacuole targeting; GABARAP, GABA type A receptor-associated protein; MAP1LC3/ LC3, microtubule associated protein 1 light chain 3; miRNA, microRNA; mRNA, messenger RNA; MTOR, mechanistic target of rapamycin kinase; NMD, nonsense-mediated decay; qRT-PCR, quantitative real-time PCR; SG, stress granule; siRNA, small interfering RNA; TOR, target of rapamycin; TORC1, TOR complex 1; Ubl, ubiquitin-like; UTR, untranslated region This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/wrna.1522 1 This article is protected by copyright. All rights reserved. Running title: Autophagy regulation by RNA decay Abstract Cells must dynamically adapt to altered environmental conditions, particularly during times of stress, to ensure their ability to function effectively and survive. The macroautophagy/autophagy pathway is highly conserved across eukaryotic cells and promotes cell survival during stressful conditions. In general, basal autophagy occurs at a low level to sustain cellular homeostasis and metabolism. -
Autophagy: from Basic Science to Clinical Application
nature publishing group REVIEW See COMMENTARY page XX Autophagy: from basic science to clinical application J Va n L i m b e r g e n 1 , 2 , 3 , C S t e v e n s 4 , E R N i m m o 1 , D C W i l s o n 2 , 3 a n d J S a t s a n g i 1 Autophagy is a cellular pathway involved in protein and organelle degradation, which is likely to represent an innate adaptation to starvation. In times of nutrient deficiency, the cell can self-digest and recycle some nonessential components through nonselective autophagy, thus sustaining minimal growth requirements until a food source becomes available. Over recent years, autophagy has been implicated in an increasing number of clinical scenarios, notably infectious diseases, cancer, neurodegenerative diseases, and autoimmunity. The recent identification of the importance of autophagy genes in the genetic susceptibility to Crohn ’ s disease suggests that a selective autophagic response may play a crucial role in the pathogenesis of common complex immune-mediated diseases. In this review, we discuss the autophagic mechanisms, their molecular regulation, and summarize their clinical relevance. This progress has led to great interest in the therapeutic potential of manipulation of both selective and nonselective autophagy in established disease. INTRODUCTION The ability to adapt to environmental change is essential for sur- Autophagy encompasses several distinct processes involving vival. This is true for the organism as a whole and for individual the delivery of portions of the cytoplasm to the lysosome for cells alike. -
Combinatorial Genomic Data Refute the Human Chromosome 2 Evolutionary Fusion and Build a Model of Functional Design for Interstitial Telomeric Repeats
The Proceedings of the International Conference on Creationism Volume 8 Print Reference: Pages 222-228 Article 32 2018 Combinatorial Genomic Data Refute the Human Chromosome 2 Evolutionary Fusion and Build a Model of Functional Design for Interstitial Telomeric Repeats Jeffrey P. Tomkins Institute for Creation Research Follow this and additional works at: https://digitalcommons.cedarville.edu/icc_proceedings Part of the Biology Commons, and the Genomics Commons DigitalCommons@Cedarville provides a publication platform for fully open access journals, which means that all articles are available on the Internet to all users immediately upon publication. However, the opinions and sentiments expressed by the authors of articles published in our journals do not necessarily indicate the endorsement or reflect the views of DigitalCommons@Cedarville, the Centennial Library, or Cedarville University and its employees. The authors are solely responsible for the content of their work. Please address questions to [email protected]. Browse the contents of this volume of The Proceedings of the International Conference on Creationism. Recommended Citation Tomkins, J.P. 2018. Combinatorial genomic data refute the human chromosome 2 evolutionary fusion and build a model of functional design for interstitial telomeric repeats. In Proceedings of the Eighth International Conference on Creationism, ed. J.H. Whitmore, pp. 222–228. Pittsburgh, Pennsylvania: Creation Science Fellowship. Tomkins, J.P. 2018. Combinatorial genomic data refute the human chromosome 2 evolutionary fusion and build a model of functional design for interstitial telomeric repeats. In Proceedings of the Eighth International Conference on Creationism, ed. J.H. Whitmore, pp. 222–228. Pittsburgh, Pennsylvania: Creation Science Fellowship. COMBINATORIAL GENOMIC DATA REFUTE THE HUMAN CHROMOSOME 2 EVOLUTIONARY FUSION AND BUILD A MODEL OF FUNCTIONAL DESIGN FOR INTERSTITIAL TELOMERIC REPEATS Jeffrey P. -
Vocabulario De Morfoloxía, Anatomía E Citoloxía Veterinaria
Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) Servizo de Normalización Lingüística Universidade de Santiago de Compostela COLECCIÓN VOCABULARIOS TEMÁTICOS N.º 4 SERVIZO DE NORMALIZACIÓN LINGÜÍSTICA Vocabulario de Morfoloxía, anatomía e citoloxía veterinaria (galego-español-inglés) 2008 UNIVERSIDADE DE SANTIAGO DE COMPOSTELA VOCABULARIO de morfoloxía, anatomía e citoloxía veterinaria : (galego-español- inglés) / coordinador Xusto A. Rodríguez Río, Servizo de Normalización Lingüística ; autores Matilde Lombardero Fernández ... [et al.]. – Santiago de Compostela : Universidade de Santiago de Compostela, Servizo de Publicacións e Intercambio Científico, 2008. – 369 p. ; 21 cm. – (Vocabularios temáticos ; 4). - D.L. C 2458-2008. – ISBN 978-84-9887-018-3 1.Medicina �������������������������������������������������������������������������veterinaria-Diccionarios�������������������������������������������������. 2.Galego (Lingua)-Glosarios, vocabularios, etc. políglotas. I.Lombardero Fernández, Matilde. II.Rodríguez Rio, Xusto A. coord. III. Universidade de Santiago de Compostela. Servizo de Normalización Lingüística, coord. IV.Universidade de Santiago de Compostela. Servizo de Publicacións e Intercambio Científico, ed. V.Serie. 591.4(038)=699=60=20 Coordinador Xusto A. Rodríguez Río (Área de Terminoloxía. Servizo de Normalización Lingüística. Universidade de Santiago de Compostela) Autoras/res Matilde Lombardero Fernández (doutora en Veterinaria e profesora do Departamento de Anatomía e Produción Animal. -
PEX5 Regulates Autophagy Via the Mtorc1-TFEB Axis During Starvation
Eun et al. Experimental & Molecular Medicine (2018) 50:4 DOI 10.1038/s12276-017-0007-8 Experimental & Molecular Medicine ARTICLE Open Access PEX5 regulates autophagy via the mTORC1-TFEB axis during starvation So Young Eun1,JoonNoLee2,In-KooNam2, Zhi-qiang Liu1,Hong-SeobSo 1, Seong-Kyu Choe1 and RaeKil Park2 Abstract Defects in the PEX5 gene impair the import of peroxisomal matrix proteins, leading to nonfunctional peroxisomes and other associated pathological defects such as Zellweger syndrome. Although PEX5 regulates autophagy process in a stress condition, the mechanisms controlling autophagy by PEX5 under nutrient deprivation are largely unknown. Herein, we show a novel function of PEX5 in the regulation of autophagy via Transcription Factor EB (TFEB). Under serum-starved conditions, when PEX5 is depleted, the mammalian target of rapamycin (mTORC1) inhibitor TSC2 is downregulated, which results in increased phosphorylation of the mTORC1 substrates, including 70S6K, S6K, and 4E- BP-1. mTORC1 activation further suppresses the nuclear localization of TFEB, as indicated by decreased mRNA levels of TFEB, LIPA, and LAMP1. Interestingly, peroxisomal mRNA and protein levels are also reduced by TFEB inactivation, indicating that TFEB might control peroxisome biogenesis at a transcriptional level. Conversely, pharmacological inhibition of mTOR resulting from PEX5 depletion during nutrient starvation activates TFEB by promoting nuclear localization of the protein. In addition, mTORC1 inhibition recovers the damaged-peroxisome biogenesis. These data suggest that PEX5 may be a critical regulator of lysosomal gene expression and autophagy through the mTOR-TFEB- autophagy axis under nutrient deprivation. 1234567890():,; 1234567890():,; Introduction Mitochondrial antiviral-signaling protein (MAVS) func- Peroxisome is an essential cellular organelle for per- tions as an antiviral signaling platform to induce the forming various metabolic activities, including oxidation interferon-independent signaling pathways4. -
Research Article Label-Free Proteomics of the Fetal Pancreas Identifies Deficits in the Peroxisome in Rats with Intrauterine Growth Restriction
Hindawi Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 1520753, 15 pages https://doi.org/10.1155/2019/1520753 Research Article Label-Free Proteomics of the Fetal Pancreas Identifies Deficits in the Peroxisome in Rats with Intrauterine Growth Restriction Xiaomei Liu ,1 Yanyan Guo ,1 Jun Wang ,1,2 Linlin Gao ,3 and Caixia Liu 1 1Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, China 2Department of Obstetrics and Gynecology, Benxi Central Hospital of China Medical University, Benxi 117022, China 3Medical Research Center, Shengjing Hospital, China Medical University, Shenyang 110004, China Correspondence should be addressed to Xiaomei Liu; [email protected] Received 14 May 2019; Revised 31 August 2019; Accepted 9 September 2019; Published 3 November 2019 Guest Editor: Roberta Cascella Copyright © 2019 Xiaomei Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Aim. The objective of the present study was to identify differentially expressed proteins (DEPs) in the pancreas of a fetus with intrauterine growth restriction (IUGR) and to investigate the molecular mechanisms leading to adulthood diabetes in IUGR. Methods. The IUGR rat model was induced by maternal protein malnutrition. The fetal pancreas was collected at embryonic day 20 (E20). Protein was extracted, pooled, and subjected to label-free quantitative proteomic analysis. Bioinformatics analysis (GO and IPA) was performed to define the pathways and networks associated with DEPs. LC-MS results were confirmed by western blotting and/or quantitative PCR (q-PCR). -
ATG9 Regulates Autophagosome Progression from the Endoplasmic Reticulum in Arabidopsis
ATG9 regulates autophagosome progression from the endoplasmic reticulum in Arabidopsis Xiaohong Zhuanga,b,1, Kin Pan Chunga,b,1, Yong Cuia,b,1, Weili Lina,b, Caiji Gaoa,b,2, Byung-Ho Kanga,b, and Liwen Jianga,b,c,3 aCentre for Cell & Developmental Biology, School of Life Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China; bState Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China; and cThe Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China Edited by Diane C. Bassham, Iowa State University, Ames, IA, and accepted by Editorial Board Member Maarten J. Chrispeels December 8, 2016 (received for review October 6, 2016) Autophagy is a conserved pathway for bulk degradationofcytoplasmic autophagy pathway because ATG9 was required for the biogenesis material by a double-membrane structure named the autophagosome. of ER-derived compartments during the unfolded protein response The initiation of autophagosome formation requires the recruitment of (9). However, whether ATG9 plays a direct role in the early stages autophagy-related protein 9 (ATG9) vesicles to the preautophagosomal of autophagosome formation or in a specific autophagy process structure. However, the functional relationship between ATG9 vesicles remainstobeinvestigatedinplants.Onemajorchallengeisthelack and the phagophore is controversial in different systems, and the mo- of morphologically informative visualization that might correlate the lecular function of ATG9 remains unknown in plants. Here, we demon- early autophagosomal structures and ATG9 vesicles in real-time and strate that ATG9 is essential for endoplasmic reticulum (ER)-derived in three dimensions. autophagosome formation in plants. -
Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity
International Journal of Molecular Sciences Review Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity Yannick Das, Daniëlle Swinkels and Myriam Baes * Lab of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; [email protected] (Y.D.); [email protected] (D.S.) * Correspondence: [email protected] Abstract: Peroxisomes are multifunctional organelles, well known for their role in cellular lipid homeostasis. Their importance is highlighted by the life-threatening diseases caused by peroxisomal dysfunction. Importantly, most patients suffering from peroxisomal biogenesis disorders, even those with a milder disease course, present with a number of ocular symptoms, including retinopathy. Patients with a selective defect in either peroxisomal α- or β-oxidation or ether lipid synthesis also suffer from vision problems. In this review, we thoroughly discuss the ophthalmological pathology in peroxisomal disorder patients and, where possible, the corresponding animal models, with a special emphasis on the retina. In addition, we attempt to link the observed retinal phenotype to the underlying biochemical alterations. It appears that the retinal pathology is highly variable and the lack of histopathological descriptions in patients hampers the translation of the findings in the mouse models. Furthermore, it becomes clear that there are still large gaps in the current knowledge on the contribution of the different metabolic disturbances to the retinopathy, but branched chain fatty acid accumulation and impaired retinal PUFA homeostasis are likely important factors. Citation: Das, Y.; Swinkels, D.; Baes, Keywords: peroxisome; Zellweger; metabolism; fatty acid; retina M. Peroxisomal Disorders and Their Mouse Models Point to Essential Roles of Peroxisomes for Retinal Integrity. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase