Rab7a and Mitophagosome Formation
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The Endocytic Membrane Trafficking Pathway Plays a Major Role
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Liverpool Repository RESEARCH ARTICLE The Endocytic Membrane Trafficking Pathway Plays a Major Role in the Risk of Parkinson’s Disease Sara Bandres-Ciga, PhD,1,2 Sara Saez-Atienzar, PhD,3 Luis Bonet-Ponce, PhD,4 Kimberley Billingsley, MSc,1,5,6 Dan Vitale, MSc,7 Cornelis Blauwendraat, PhD,1 Jesse Raphael Gibbs, PhD,7 Lasse Pihlstrøm, MD, PhD,8 Ziv Gan-Or, MD, PhD,9,10 The International Parkinson’s Disease Genomics Consortium (IPDGC), Mark R. Cookson, PhD,4 Mike A. Nalls, PhD,1,11 and Andrew B. Singleton, PhD1* 1Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 2Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain 3Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 4Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 5Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom 6Department of Pathophysiology, University of Tartu, Tartu, Estonia 7Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 8Department of Neurology, Oslo University Hospital, Oslo, Norway 9Department of Neurology and Neurosurgery, Department of Human Genetics, McGill University, Montréal, Quebec, Canada 10Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada 11Data Tecnica International, Glen Echo, Maryland, USA ABSTRACT studies, summary-data based Mendelian randomization Background: PD is a complex polygenic disorder. -
Primate Specific Retrotransposons, Svas, in the Evolution of Networks That Alter Brain Function
Title: Primate specific retrotransposons, SVAs, in the evolution of networks that alter brain function. Olga Vasieva1*, Sultan Cetiner1, Abigail Savage2, Gerald G. Schumann3, Vivien J Bubb2, John P Quinn2*, 1 Institute of Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, U.K 2 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK 3 Division of Medical Biotechnology, Paul-Ehrlich-Institut, Langen, D-63225 Germany *. Corresponding author Olga Vasieva: Institute of Integrative Biology, Department of Comparative genomics, University of Liverpool, Liverpool, L69 7ZB, [email protected] ; Tel: (+44) 151 795 4456; FAX:(+44) 151 795 4406 John Quinn: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, The University of Liverpool, Liverpool L69 3BX, UK, [email protected]; Tel: (+44) 151 794 5498. Key words: SVA, trans-mobilisation, behaviour, brain, evolution, psychiatric disorders 1 Abstract The hominid-specific non-LTR retrotransposon termed SINE–VNTR–Alu (SVA) is the youngest of the transposable elements in the human genome. The propagation of the most ancient SVA type A took place about 13.5 Myrs ago, and the youngest SVA types appeared in the human genome after the chimpanzee divergence. Functional enrichment analysis of genes associated with SVA insertions demonstrated their strong link to multiple ontological categories attributed to brain function and the disorders. SVA types that expanded their presence in the human genome at different stages of hominoid life history were also associated with progressively evolving behavioural features that indicated a potential impact of SVA propagation on a cognitive ability of a modern human. -
Mitochondrial Rab Gaps Govern Autophagosome Biogenesis During Mitophagy Koji Yamano1, Adam I Fogel1, Chunxin Wang1, Alexander M Van Der Bliek2, Richard J Youle1*
RESEARCH ARTICLE elife.elifesciences.org Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy Koji Yamano1, Adam I Fogel1, Chunxin Wang1, Alexander M van der Bliek2, Richard J Youle1* 1Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States; 2Department of Biological Chemistry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, United States Abstract Damaged mitochondria can be selectively eliminated by mitophagy. Although two gene products mutated in Parkinson’s disease, PINK1, and Parkin have been found to play a central role in triggering mitophagy in mammals, how the pre-autophagosomal isolation membrane selectively and accurately engulfs damaged mitochondria remains unclear. In this study, we demonstrate that TBC1D15, a mitochondrial Rab GTPase-activating protein (Rab-GAP), governs autophagosome biogenesis and morphology downstream of Parkin activation. To constrain autophagosome morphogenesis to that of the cargo, TBC1D15 inhibits Rab7 activity and associates with both the mitochondria through binding Fis1 and the isolation membrane through the interactions with LC3/ GABARAP family members. Another TBC family member TBC1D17, also participates in mitophagy and forms homodimers and heterodimers with TBC1D15. These results demonstrate that TBC1D15 and TBC1D17 mediate proper autophagic encapsulation of mitochondria by regulating Rab7 activity at the interface between mitochondria and isolation membranes. DOI: 10.7554/eLife.01612.001 *For correspondence: [email protected] Introduction Competing interests: See page 21 Autophagosomes enclose seemingly random portions of the cytoplasm to supply nutrients during starvation or they can specifically engulf cellular debris to maintain quality control (Mizushima et al., Funding: See page 21 2011). -
Role of the V1G1 Subunit of V-Atpase in Breast Cancer Cell Migration
www.nature.com/scientificreports OPEN Role of the V1G1 subunit of V‑ATPase in breast cancer cell migration Maria De Luca*, Roberta Romano & Cecilia Bucci* V‑ATPase is a large multi‑subunit complex that regulates acidity of intracellular compartments and of extracellular environment. V‑ATPase consists of several subunits that drive specifc regulatory mechanisms. The V1G1 subunit, a component of the peripheral stalk of the pump, controls localization and activation of the pump on late endosomes and lysosomes by interacting with RILP and RAB7. Deregulation of some subunits of the pump has been related to tumor invasion and metastasis formation in breast cancer. We observed a decrease of V1G1 and RAB7 in highly invasive breast cancer cells, suggesting a key role of these proteins in controlling cancer progression. Moreover, in MDA‑MB‑231 cells, modulation of V1G1 afected cell migration and matrix metalloproteinase activation in vitro, processes important for tumor formation and dissemination. In these cells, characterized by high expression of EGFR, we demonstrated that V1G1 modulates EGFR stability and the EGFR downstream signaling pathways that control several factors required for cell motility, among which RAC1 and coflin. In addition, we showed a key role of V1G1 in the biogenesis of endosomes and lysosomes. Altogether, our data describe a new molecular mechanism, controlled by V1G1, required for cell motility and that promotes breast cancer tumorigenesis. Vacuolar H+-ATPase (V-ATPase) is a multi-subunit complex that mediates transport of protons across intracel- lular and plasma membranes via an ATP-dependent mechanism1–3. V-ATPase is composed of several subunits organized in two domains, the V1 cytosolic and the V0 membrane-integral. -
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Charcot-Marie-Tooth Type 2B: a New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation
cells Article Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation Paola Saveri 1, Maria De Luca 2 , Veronica Nisi 2, Chiara Pisciotta 1, Roberta Romano 2 , Giuseppe Piscosquito 3, Mary M. Reilly 4, James M. Polke 5, Tiziana Cavallaro 6, Gian Maria Fabrizi 6, Paola Fossa 7 , Elena Cichero 7, Raffaella Lombardi 1, Giuseppe Lauria 1,8, Stefania Magri 9 , Franco Taroni 9 , Davide Pareyson 1,* and Cecilia Bucci 2,* 1 Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy; [email protected] (P.S.); [email protected] (C.P.); raff[email protected] (R.L.); [email protected] (G.L.) 2 Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy; [email protected] (M.D.L.); [email protected] (V.N.); [email protected] (R.R.) 3 Functional Neuromotor Rehabilitation Unit, IRCCS ICS Maugeri Spa-SB, Scientific Institute of Telese Terme, 82037 Telese Terme (Benevento), Italy; [email protected] 4 MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK; [email protected] 5 Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery, UCL Institute of Neurology, London WC1N 3BG, UK; [email protected] 6 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy; [email protected] -
Regulation of Mitochondrial Dynamics and Cell Fate Rimpy Dhingra, Phd; Lorrie A
Advance Publication by-J-STAGE Circulation Journal REVIEW Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Regulation of Mitochondrial Dynamics and Cell Fate Rimpy Dhingra, PhD; Lorrie A. Kirshenbaum, PhD Though the mitochondrion was initially identified as a key organelle essentially required for energy production and oxidative metabolism, there is considerable evidence that mitochondria are intimately involved in regulating vital cellular processes, such as programmed cell death, proliferation and autophagy. Discovery of mitochondrial “shaping proteins” (Dynamin-related protein (Drp), mitofusins (Mfn) etc.) has revealed that mitochondria are highly dynamic organelles continually changing morphology by fission and fusion processes. Several human pathologies, including cancer, Parkinson’s disease, Alzheimer’s disease and cardiovascular diseases, have been linked to abnormalities in proteins that govern mitochondrial fission or fusion respectively. Notably, in the context of the heart, defects in mitochondrial dynamics resulting in too many fused and/or fragmented mitochondria have been associated with impaired cardiac development, autophagy, and contractile dysfunction. Understanding the mechanisms that govern mitochondrial fission/ fusion is paramount in developing new treatment strategies for human diseases in which defects in fission or fusion is the primary underlying defect. Here, we provide a comprehensive overview of the cellular targets and molecular signal- ing pathways that govern mitochondrial dynamics -
Rab7a: the Master Regulator of Vesicular Trafficking
Biomedical Reviews 2014; 25: 67-81 © Bul garian Society for Cell Biology ISSN 1314-1929 (online) RAB7A: THE MASTER REGULATOR OF VESICULAR TRAFFICKING Soumik BasuRay Eugene McDermott Center for Human Growth and Development, Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA The membrane flow of eukaryotic cells occurs through vesicles that bud from a donor compartment, move and fuse with an ac- ceptor compartment. Rab (Ras-related in brain), which belong to the Ras superfamily of small GTPases, emerged as a central player of vesicle mobility in both secretory and endocytic pathway, Rab7a being a master regulator of late endocytic trafficking. Elucidation of how mutant or dysregulated Rab7 GTPase and accessory proteins contribute to organ specific and systemic dis- ease remains an area of intensive study and an essential foundation for effective drug targeting. Mutation of Rab7 or associated regulatory proteins causes numerous human genetic diseases. Cancer and neurodegeneration represent examples of acquired human diseases resulting from the up- or down-regulation or aberrant function of Rab7. The broad range of physiologic pro- cesses affected by altered Rab7 activity is based on its pivotal roles in membrane trafficking and signaling. The Rab7-regulated processes of cargo sorting, cytoskeletal translocation of vesicles and appropriate docking and fusion with the target membranes control cell metabolism, growth and differentiation. In this review, role of Rab7 in endocytosis is evaluated to illustrate normal function and the consequences of dysregulation resulting in human disease. Selected examples are designed to illustrate how defects in Rab7 activity alter endocytic trafficking that underlie neurologic, lipid storage, and bone disorders as well as cancer. -
The Role of Autophagy in Tumour Development and Cancer Therapy
expert reviews http://www.expertreviews.org/ in molecular medicine The role of autophagy in tumour development and cancer therapy Mathias T. Rosenfeldt and Kevin M. Ryan* Autophagy is a catabolic membrane-trafficking process that leads to sequestration and degradation of intracellular material within lysosomes. It is executed at basal levels in every cell and promotes cellular homeostasis by and cancer therapy regulating organelle and protein turnover. In response to various forms of cellular stress, however, the levels and cargoes of autophagy can be modulated. In nutrient-deprived states, for example, autophagy can be activated to degrade cargoes for cell-autonomous energy production to promote cell survival. In other contexts, in contrast, autophagy has been shown to contribute to cell death. Given these dual effects in regulating cell viability, it is no surprise that autophagy has implications in both the genesis and treatment of malignant disease. In this review, we provide a comprehensive appraisal of the way in which oncogenes and tumour suppressor genes regulate autophagy. In addition, we address the current evidence from human cancer and animal models that has aided our understanding of the role of autophagy in tumour progression. Finally, the potential for targeting autophagy therapeutically is discussed in light of the functions of autophagy at different stages of tumour progression and in The role of autophagy in tumour development normal tissues. During the genesis of cancer, tumour cells these demands, through the lysosomal-mediated experience various forms of intracellular and degradation of cellular proteins and organelles. extracellular stress. This hostile situation results in This not only results in the removal of damaged damage to cellular proteins, the production of cellular constituents, but also, where required, reactive oxygen species (ROS) and the replication can provide the catabolic intermediates for of cells with heritable DNA damage. -
A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection
CLINICAL RESEARCH www.jasn.org A Peripheral Blood Gene Expression Signature to Diagnose Subclinical Acute Rejection Weijia Zhang,1 Zhengzi Yi,1 Karen L. Keung,2 Huimin Shang,3 Chengguo Wei,1 Paolo Cravedi,1 Zeguo Sun,1 Caixia Xi,1 Christopher Woytovich,1 Samira Farouk,1 Weiqing Huang,1 Khadija Banu,1 Lorenzo Gallon,4 Ciara N. Magee,5 Nader Najafian,5 Milagros Samaniego,6 Arjang Djamali ,7 Stephen I. Alexander,2 Ivy A. Rosales,8 Rex Neal Smith,8 Jenny Xiang,3 Evelyne Lerut,9 Dirk Kuypers,10,11 Maarten Naesens ,10,11 Philip J. O’Connell,2 Robert Colvin,8 Madhav C. Menon,1 and Barbara Murphy1 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Background In kidney transplant recipients, surveillance biopsies can reveal, despite stable graft function, histologic features of acute rejection and borderline changes that are associated with undesirable graft outcomes. Noninvasive biomarkers of subclinical acute rejection are needed to avoid the risks and costs associated with repeated biopsies. Methods We examined subclinical histologic and functional changes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study who underwent surveillance biopsies over 2 years, identifying those with subclinical or borderline acute cellular rejection (ACR) at 3 months (ACR-3) post-transplant. We performed RNA sequencing on whole blood collected from 88 indi- viduals at the time of 3-month surveillance biopsy to identify transcripts associated with ACR-3, developed a novel sequencing-based targeted expression assay, and validated this gene signature in an independent cohort. -
LRRK1 Phosphorylation of Rab7 at S72 Links Trafficking of EGFR
© 2019. Published by The Company of Biologists Ltd | Journal of Cell Science (2019) 132, jcs228809. doi:10.1242/jcs.228809 RESEARCH ARTICLE LRRK1 phosphorylation of Rab7 at S72 links trafficking of EGFR- containing endosomes to its effector RILP Hiroshi Hanafusa1,*, Takuya Yagi1, Haruka Ikeda1, Naoki Hisamoto1, Tomoki Nishioka2, Kozo Kaibuchi2, Kyoko Shirakabe3 and Kunihiro Matsumoto1,* ABSTRACT active form and a cytosolic, GDP-bound, inactive form. The active, Ligand-induced activation of epidermal growth factor receptor (EGFR) GTP-bound Rab protein binds to various effectors to regulate initiates trafficking events that re-localize the receptor from the cell membrane trafficking (Hutagalung and Novick, 2011; Stenmark, surface to intracellular endocytic compartments. EGFR-containing 2009). Rab7 (herein referring to Rab7a) is a member of the Rab endosomes are transported to lysosomes for degradation by the family that has been demonstrated to play a crucial role in regulating dynein–dynactin motor protein complex. However, this cargo- endo-lysosomal membrane traffic (Guerra and Bucci, 2016). During dependent endosomal trafficking mechanism remains largely the early-to-late endosome transition, Rab7 is recruited to the uncharacterized. Here, we show that GTP-bound Rab7 is subdomains of early endosomes bearing Rab5, followed by Rab5 phosphorylated on S72 by leucine-rich repeat kinase 1 (LRRK1) at the displacement from the same endosome and the acquirement of endosomal membrane. This phosphorylation promotes the interaction of Rab7-mediated transport capacity (Pfeffer, 2013; Poteryaev et al., Rab7 (herein referring to Rab7a) with its effector RILP, resulting in 2010; Rink et al., 2005). Rab7 regulates the movement of recruitment of the dynein–dynactin complex to Rab7-positive vesicles. -
Rab5 and Rab4 Regulate Axon Elongation in Thexenopus Visual System
The Journal of Neuroscience, January 8, 2014 • 34(2):373–391 • 373 Cellular/Molecular Rab5 and Rab4 Regulate Axon Elongation in the Xenopus Visual System Julien Falk, Filip A. Konopacki, Krishna H. Zivraj, and Christine E. Holt Department of Physiology, Development, and Neuroscience, Anatomy Building, University of Cambridge, Cambridge CB2 3DY, United Kingdom The elongation rate of axons is tightly regulated during development. Recycling of the plasma membrane is known to regulate axon extension; however, the specific molecules involved in recycling within the growth cone have not been fully characterized. Here, we investigated whether the small GTPases Rab4 and Rab5 involved in short-loop recycling regulate the extension of Xenopus retinal axons. We report that, in growth cones, Rab5 and Rab4 proteins localize to endosomes, which accumulate markers that are constitutively recycled. Fluorescence recovery after photo-bleaching experiments showed that Rab5 and Rab4 are recruited to endosomes in the growth cone, suggesting that they control recycling locally. Dynamic image analysis revealed that Rab4-positive carriers can bud off from Rab5 endosomes and move to the periphery of the growth cone, suggesting that both Rab5 and Rab4 contribute to recycling within the growth cone. Inhibition of Rab4 function with dominant-negative Rab4 or Rab4 morpholino and constitutive activation of Rab5 decreases the elongation of retinal axons in vitro and in vivo, but, unexpectedly, does not disrupt axon pathfinding. Thus, Rab5- and Rab4-mediated control of endosome trafficking appears to be crucial for axon growth. Collectively, our results suggest that recycling from Rab5-positive endosomes via Rab4 occurs within the growth cone and thereby supports axon elongation.