Attenuation of Cgas/STING Activity During Mitosis
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Barlow et al. BMC Biology (2018) 16:27 https://doi.org/10.1186/s12915-018-0492-9 RESEARCHARTICLE Open Access A sophisticated, differentiated Golgi in the ancestor of eukaryotes Lael D. Barlow1, Eva Nývltová2,3, Maria Aguilar1, Jan Tachezy2 and Joel B. Dacks1,4* Abstract Background: The Golgi apparatus is a central meeting point for the endocytic and exocytic systems in eukaryotic cells, and the organelle’s dysfunction results in human disease. Its characteristic morphology of multiple differentiated compartments organized into stacked flattened cisternae is one of the most recognizable features of modern eukaryotic cells, and yet how this is maintained is not well understood. The Golgi is also an ancient aspect of eukaryotes, but the extent and nature of its complexity in the ancestor of eukaryotes is unclear. Various proteins have roles in organizing the Golgi, chief among them being the golgins. Results: We address Golgi evolution by analyzing genome sequences from organisms which have lost stacked cisternae as a feature of their Golgi and those that have not. Using genomics and immunomicroscopy, we first identify Golgi in the anaerobic amoeba Mastigamoeba balamuthi. We then searched 87 genomes spanning eukaryotic diversity for presence of the most prominent proteins implicated in Golgi structure, focusing on golgins. We show some candidates as animal specific and others as ancestral to eukaryotes. Conclusions: None of the proteins examined show a phyletic distribution that correlates with the morphology of stacked cisternae, suggesting the possibility of stacking as an emergent property. Strikingly, however, the combination of golgins conserved among diverse eukaryotes allows for the most detailed reconstruction of the organelle to date, showing a sophisticated Golgi with differentiated compartments and trafficking pathways in the common eukaryotic ancestor. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
S41467-020-18249-3.Pdf
ARTICLE https://doi.org/10.1038/s41467-020-18249-3 OPEN Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain Lei Zhao1,2,17, Zhongqi Li 1,2,17, Joaquim S. L. Vong2,3,17, Xinyi Chen1,2, Hei-Ming Lai1,2,4,5,6, Leo Y. C. Yan1,2, Junzhe Huang1,2, Samuel K. H. Sy1,2,7, Xiaoyu Tian 8, Yu Huang 8, Ho Yin Edwin Chan5,9, Hon-Cheong So6,8, ✉ ✉ Wai-Lung Ng 10, Yamei Tang11, Wei-Jye Lin12,13, Vincent C. T. Mok1,5,6,14,15 &HoKo 1,2,4,5,6,8,14,16 1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovas- cular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation- dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which pro- minently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed tran- scriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible. -
Golgi Matrix Proteins Interact with P24 Cargo Receptors and Aid Their Efficient Retention in the Golgi Apparatus
Published December 10, 2001 JCBReport Golgi matrix proteins interact with p24 cargo receptors and aid their efficient retention in the Golgi apparatus Francis A. Barr, Christian Preisinger, Robert Kopajtich, and Roman Körner Department of Cell Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany he Golgi apparatus is a highly complex organelle in vivo. GRASPs interact directly with the cytoplasmic comprised of a stack of cisternal membranes on the domains of specific p24 cargo receptors depending on T secretory pathway from the ER to the cell surface. their oligomeric state, and mutation of the GRASP binding This structure is maintained by an exoskeleton or Golgi site in the cytoplasmic tail of one of these, p24a, results in it matrix constructed from a family of coiled-coil proteins, being transported to the cell surface. These results suggest the golgins, and other peripheral membrane components that one function of the Golgi matrix is to aid efficient such as GRASP55 and GRASP65. Here we find that TMP21, retention or sequestration of p24 cargo receptors and other Downloaded from p24a, and gp25L, members of the p24 cargo receptor family, membrane proteins in the Golgi apparatus. are present in complexes with GRASP55 and GRASP65 Introduction on April 13, 2017 The Golgi apparatus is an organelle on the secretory pathway required to target it to the Golgi (Barr et al., 1998). GM130 required for the processing of complex sugar structures on in turn is a receptor for p115, required for tethering vesicles many proteins and lipids, and for the sorting of these proteins to their target membrane (Barroso et al., 1995; Nakamura et and lipids to their correct subcellular destinations (Farquhar al., 1997). -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
Signature Redacted Thesis Supervisor Certified By
Single-Cell Transcriptomics of the Mouse Thalamic Reticular Nucleus by Taibo Li S.B., Massachusetts Institute of Technology (2015) Submitted to the Department of Electrical Engineering and Computer Science in partial fulfillment of the requirements for the degree of Master of Engineering in Electrical Engineering and Computer Science at the MASSACHUSETTS INSTITUTE OF TECHNOLOGY June 2017 @ Massachusetts Institute of Technology 2017. All rights reserved. A uthor ... ..................... Department of Electrical Engineering and Computer Science May 25, 2017 Certified by. 3ignature redacted Guoping Feng Poitras Professor of Neuroscience, MIT Signature redacted Thesis Supervisor Certified by... Kasper Lage Assistant Professor, Harvard Medical School Thesis Supervisor Accepted by . Signature redacted Christopher Terman Chairman, Masters of Engineering Thesis Committee MASSACHUSETTS INSTITUTE 0) OF TECHNOLOGY w AUG 14 2017 LIBRARIES 2 Single-Cell Transcriptomics of the Mouse Thalamic Reticular Nucleus by Taibo Li Submitted to the Department of Electrical Engineering and Computer Science on May 25, 2017, in partial fulfillment of the requirements for the degree of Master of Engineering in Electrical Engineering and Computer Science Abstract The thalamic reticular nucleus (TRN) is strategically located at the interface between the cortex and the thalamus, and plays a key role in regulating thalamo-cortical in- teractions. Current understanding of TRN neurobiology has been limited due to the lack of a comprehensive survey of TRN heterogeneity. In this thesis, I developed an integrative computational framework to analyze the single-nucleus RNA sequencing data of mouse TRN in a data-driven manner. By combining transcriptomic, genetic, and functional proteomic data, I discovered novel insights into the molecular mecha- nisms through which TRN regulates sensory gating, and suggested targeted follow-up experiments to validate these findings. -
Crystal Structures of the Single PDZ Domains from GRASP65 and Their Interaction with the Golgin GM130
ORIGINAL SCIENTIFIC PAPER Croat. Chem. Acta 2018, 91(2), 255–264 Published online: July 11, 2018 DOI: 10.5562/cca3341 Crystal Structures of the Single PDZ Domains from GRASP65 and their Interaction with the Golgin GM130 Claudia M. Jurk,1 Yvette Roske,1 Udo Heinemann1,2,* 1 Macromolecular Structure and Interaction Laboratory, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany 2 Institute of Chemistry and Biochemistry, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany * Corresponding author’s e-mail address: [email protected] RECEIVED: April 12, 2018 REVISED: June 19, 2018 ACCEPTED: June 19, 2018 THIS PAPER IS DEDICATED TO DR. BISERKA K -P ON THE OCCASION OF HER 80TH BIRTHDAY OJIĆ RODIĆ Abstract: Among the major components of the Golgi apparatus are the GRASP family proteins, including GRASP65 on the cis-Golgi side. With its GRASP domain, GRASP65 is involved in Golgi stacking and ribbon formation. Interaction of GRASP65 with the Golgi marker protein GM130 is important for the docking of vesicles to the Golgi membrane. We present here structures of the two individual PDZ domains comprising the GRASP domain in human GRASP65. We use isothermal titration calorimetry to probe the interaction between GRASP65 and GM130. Additionally, we present evidence for the limited sequence conservation of the PDZ fold by describing the PDZ domain structure of the GRASP65 homolog Grh1 from Saccharomyces cerevisiae. Keywords: PDZ domain structure, Golgi stacking, GRASP family, Golgins, Golgi apparatus, -
The Genetics of Bipolar Disorder
Molecular Psychiatry (2008) 13, 742–771 & 2008 Nature Publishing Group All rights reserved 1359-4184/08 $30.00 www.nature.com/mp FEATURE REVIEW The genetics of bipolar disorder: genome ‘hot regions,’ genes, new potential candidates and future directions A Serretti and L Mandelli Institute of Psychiatry, University of Bologna, Bologna, Italy Bipolar disorder (BP) is a complex disorder caused by a number of liability genes interacting with the environment. In recent years, a large number of linkage and association studies have been conducted producing an extremely large number of findings often not replicated or partially replicated. Further, results from linkage and association studies are not always easily comparable. Unfortunately, at present a comprehensive coverage of available evidence is still lacking. In the present paper, we summarized results obtained from both linkage and association studies in BP. Further, we indicated new potential interesting genes, located in genome ‘hot regions’ for BP and being expressed in the brain. We reviewed published studies on the subject till December 2007. We precisely localized regions where positive linkage has been found, by the NCBI Map viewer (http://www.ncbi.nlm.nih.gov/mapview/); further, we identified genes located in interesting areas and expressed in the brain, by the Entrez gene, Unigene databases (http://www.ncbi.nlm.nih.gov/entrez/) and Human Protein Reference Database (http://www.hprd.org); these genes could be of interest in future investigations. The review of association studies gave interesting results, as a number of genes seem to be definitively involved in BP, such as SLC6A4, TPH2, DRD4, SLC6A3, DAOA, DTNBP1, NRG1, DISC1 and BDNF. -
ACBD3 Modulates KDEL Receptor Interaction with PKA for Its
Yue et al. BMC Biology (2021) 19:194 https://doi.org/10.1186/s12915-021-01137-7 RESEARCH ARTICLE Open Access ACBD3 modulates KDEL receptor interaction with PKA for its trafficking via tubulovesicular carrier Xihua Yue1†, Yi Qian1†, Lianhui Zhu1, Bopil Gim2, Mengjing Bao1, Jie Jia1,3, Shuaiyang Jing1,3, Yijing Wang1,3, Chuanting Tan1,3, Francesca Bottanelli4, Pascal Ziltener5, Sunkyu Choi6, Piliang Hao1 and Intaek Lee1,7* Abstract Background: KDEL receptor helps establish cellular equilibrium in the early secretory pathway by recycling leaked ER-chaperones to the ER during secretion of newly synthesized proteins. Studies have also shown that KDEL receptor may function as a signaling protein that orchestrates membrane flux through the secretory pathway. We have recently shown that KDEL receptor is also a cell surface receptor, which undergoes highly complex itinerary between trans-Golgi network and the plasma membranes via clathrin-mediated transport carriers. Ironically, however, it is still largely unknown how KDEL receptor is distributed to the Golgi at steady state, since its initial discovery in late 1980s. Results: We used a proximity-based in vivo tagging strategy to further dissect mechanisms of KDEL receptor trafficking. Our new results reveal that ACBD3 may be a key protein that regulates KDEL receptor trafficking via modulation of Arf1-dependent tubule formation. We demonstrate that ACBD3 directly interact with KDEL receptor and form a functionally distinct protein complex in ArfGAPs-independent manner. Depletion of ACBD3 results in re- localization of KDEL receptor to the ER by inducing accelerated retrograde trafficking of KDEL receptor. Importantly, this is caused by specifically altering KDEL receptor interaction with Protein Kinase A and Arf1/ArfGAP1, eventually leading to increased Arf1-GTP-dependent tubular carrier formation at the Golgi. -
Identification of Prognosis Biomarkers of Prostatic Cancer in a Cohort Of
Current Problems in Cancer 43 (2019) 100503 Contents lists available at ScienceDirect Current Problems in Cancer journal homepage: www.elsevier.com/locate/cpcancer Identification of prognosis biomarkers of prostatic cancer in a cohort of 498 patients from TCGA ∗ Zhiqiang Chen , Haiyi Hu Department of Urology, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China a b s t r a c t Objective: Prostatic cancer (PCa) is the first common cancer in male, and the prognostic variables are ben- eficial for clinical trial design and treatment strategies for PCa. This study was performed to identify more potential biomarkers for the prognosis of patients with PCa. Methods and results: The transcriptome data and survival information of a cohort including 498 subjects with PCa were downloaded from TCGA . A total of 4293 differentially expressed genes (DEGs), including 1362 prognosis-related DEGs, were identified in PCa tissues compared with normal tissues. Upregulated genes, including serine/arginine-rich splicing factors (SRSFs; such as SRSF2, SRSF5, SRSF7 and SRSF8 ), and ubiquitin conjugating enzyme E2 (UBE2) members (such as UBE2D2, UBE2G2, UBE2J1 and UBE2E1 ), were identified as negative prognostic biomarkers of PCa, as the high expression of them correlated with poor overall survival of PCa patients. Several downregulated Golgi-ER traffic mediators (such as SEC31A, TMED2, and TMED10 ) were identified as positive prognostic biomarkers of PCa, as the high expression of them correlated with good overall survival of PCa patients. Conclusions: These genes were of great interests in prognosis of PCa, and some of them may be constructive for the augmentation of clinical trial design and treatment strategies for PCa. -
Loss of the Golgin GM130 Causes Golgi Disruption, Purkinje Neuron Loss, and Ataxia in Mice
Loss of the golgin GM130 causes Golgi disruption, Purkinje neuron loss, and ataxia in mice Chunyi Liua,b,1, Mei Meia,1, Qiuling Lia,1, Peristera Robotic, Qianqian Panga,b, Zhengzhou Yinga,b, Fei Gaod, Martin Lowec,2, and Shilai Baoa,b,2 aState Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; bSchool of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China; cFaculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PT, United Kingdom; and dState Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China Edited by Jennifer Lippincott-Schwartz, Howard Hughes Medical Institute, Ashburn, VA, and approved November 28, 2016 (received for review May 27, 2016) The Golgi apparatus lies at the heart of the secretory pathway remains unclear (20). Several studies have shown that polarized where it is required for secretory trafficking and cargo modifica- membrane delivery via the Golgi apparatus is important for tion. Disruption of Golgi architecture and function has been widely neuronal morphogenesis during brain development (8–10, 21), but observed in neurodegenerative disease, but whether Golgi dys- whether impairment of this process can cause neuronal death with function is causal with regard to the neurodegenerative process, consequent neurological impairment in vivo is currently unknown. or is simply a manifestation of neuronal death, remains unclear. Members of the golgin family of coiled-coil proteins are re- Here we report that targeted loss of the golgin GM130 leads to quired for maintenance of Golgi organization and are important a profound neurological phenotype in mice. -
GRASP55, a Second Mammalian GRASP Protein Involved in the Stacking of Golgi Cisternae in a Cell-Free System
The EMBO Journal Vol.18 No.18 pp.4949–4960, 1999 GRASP55, a second mammalian GRASP protein involved in the stacking of Golgi cisternae in a cell-free system James Shorter, Rose Watson, give rise to cisternae, and in the subsequent stacking of Maria-Eleni Giannakou1, Mairi Clarke1, these cisternae to form stacks. These studies have used Graham Warren2 and Francis A.Barr1,3 in vitro assays in which the Golgi apparatus can be disassembled and reassembled under defined conditions, Cell Biology Laboratory, Imperial Cancer Research Fund, 44 Lincoln’s thus allowing the identification of components important 1 Inn Fields, London WC2A 3PX and IBLS, Division of Biochemistry for different aspects of Golgi structure (Acharya et al., and Molecular Biology, Davidson Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK 1995; Rabouille et al., 1995a). One cell-free system 2 (Rabouille et al., 1995a) has exploited the disassembly of Present address: Department of Cell Biology, SHM, C441, the Golgi apparatus into many small vesicles and mem- Yale University School of Medicine, 33 Cedar Street, PO Box 208002, New Haven, CT 06520-8002, USA brane fragments during cell division (Lucocq et al., 1987, 1989). In this system, isolated Golgi membranes are 3Corresponding author e-mail: [email protected] treated with mitotic cell cytosol to generate a population of mitotic Golgi fragments (MGFs) that can reassemble We have identified a 55 kDa protein, named GRASP55 into stacked Golgi membranes when incubated under (Golgi reassembly stacking protein of 55 kDa), as a the correct conditions. The N-ethylmaleimide (NEM)- component of the Golgi stacking machinery.