TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation
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Overexpression of RPN2 Suppresses Radiosensitivity of Glioma Cells By
Li et al. Molecular Medicine (2020) 26:43 Molecular Medicine https://doi.org/10.1186/s10020-020-00171-5 RESEARCH ARTICLE Open Access Overexpression of RPN2 suppresses radiosensitivity of glioma cells by activating STAT3 signal transduction Changyu Li1†, Haonan Ran2†, Shaojun Song1, Weisong Liu3, Wenhui Zou1, Bei Jiang4, Hongmei Zhao5 and Bin Shao6* Abstract Background: Radiation therapy is the primary method of treatment for glioblastoma (GBM). Therefore, the suppression of radioresistance in GBM cells is of enormous significance. Ribophorin II (RPN2), a protein component of an N-oligosaccharyl transferase complex, has been associated with chemotherapy drug resistance in multiple cancers, including GBM. However, it remains unclear whether this also plays a role in radiation therapy resistance in GBM. Methods: We conducted a bioinformatic analysis of RPN2 expression using the UCSC Cancer Genomics Browser and GEPIA database and performed an immunohistochemical assessment of RPN2 expression in biopsy specimens from 34 GBM patients who had received radiation-based therapy. We also studied the expression and function of RPN2 in radiation-resistant GBM cells. Results: We found that RPN2 expression was upregulated in GBM tumors and correlated with poor survival. The expression of RPN2 was also higher in GBM patients with tumor recurrence, who were classified to be resistant to radiation therapy. In the radiation-resistant GBM cells, the expression of RPN2 was also higher than in the parental cells. Depletion of RPN2 in resistant cells can sensitize these cells to radiation-induced apoptosis, and overexpression of RPN2 had the reverse effect. Myeloid cell leukemia 1 (MCL1) was found to be the downstream target of RPN2, and contributed to radiation resistance in GBM cells. -
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bioRxiv preprint doi: https://doi.org/10.1101/850776; this version posted January 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Intramembrane protease RHBDL4 cleaves oligosaccharyltransferase subunits to target them for ER-associated degradation Julia D. Knopf1, Nina Landscheidt1, Cassandra L. Pegg2, Benjamin L. Schulz2, Nathalie Kühnle1, Chao-Wei Chao1, Simon Huck1 and Marius K. Lemberg1, # 1Centre for Molecular Biology of Heidelberg University (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany. 2School of Chemistry and Molecular Biosciences, ARC Training Centre for Biopharmaceutical Innovation, The University of Queensland, St Lucia QLD 4072, Australia. #Corresponding author: [email protected] Running title: RHBDL4 triggers ERAD of OST subunits Key words: Rhomboid serine protease, Rhbdd1, ubiquitin-dependent proteolysis, post- translational protein abundance control, N-linked glycosylation. Abbreviations ERAD, ER-associated degradation; OST, oligosacharyltransferase; TM, transmembrane; UIM, ubiquitin-interacting motif. Abstract The Endoplasmic Reticulum (ER)-resident intramembrane rhomboid protease RHBDL4 generates metastable protein fragments and together with the ER-associated degradation (ERAD) machinery provides a clearance mechanism for aberrant and surplus proteins. However, the endogenous substrate spectrum and with that the role of RHBDL4 in physiological ERAD is mainly unknown. Here, we use a substrate trapping approach in combination with quantitative proteomics to identify physiological RHBDL4 substrates. This revealed oligosacharyltransferase (OST) complex subunits such as the catalytic active subunit STT3A as substrates for the RHBDL4-dependent ERAD pathway. RHBDL4-catalyzed cleavage inactivates OST subunits by triggering dislocation into the cytoplasm and subsequent proteasomal degradation. -
Tumor Suppressor Candidate 3 (TUSC3)
IJC International Journal of Cancer Tumor suppressor candidate 3 (TUSC3) prevents the epithelial- to-mesenchymal transition and inhibits tumor growth by modulating the endoplasmic reticulum stress response in ovarian cancer cells Katerina Kratochvılova1,2, Peter Horak3, Milan Esner1, Karel Soucˇek2,4,5, Dietmar Pils6, Mariam Anees3,7, Erwin Tomasich3, Frantisek Drafi 1, Veronika Jurtıkova1, Ales Hampl1, Michael Krainer3 and Petr Vanhara 1 1 Department of Histology and Embryology, Faculty of Medicine, Masaryk University, Brno, Czech Republic 2 Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne’s University Hospital, Brno, Czech Republic 3 Department of Internal Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria 4 Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Brno, Czech Republic 5 Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic 6 Department of Obstetrics and Gynecology, Molecular Oncology Group, Medical University of Vienna, Vienna, Austria 7 Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan Ovarian cancer is one of the most common malignancies in women and contributes greatly to cancer-related deaths. Tumor suppressor candidate 3 (TUSC3) is a putative tumor suppressor gene located at chromosomal region 8p22, which is often lost in epithelial cancers. Epigenetic silencing of TUSC3 has been associated with poor prognosis, and hypermethylation of its pro- moter provides an independent biomarker of overall and disease-free survival in ovarian cancer patients. TUSC3 is localized to the endoplasmic reticulum in an oligosaccharyl tranferase complex responsible for the N-glycosylation of proteins. However, the precise molecular role of TUSC3 in ovarian cancer remains unclear. -
Multi-Targeted Mechanisms Underlying the Endothelial Protective Effects of the Diabetic-Safe Sweetener Erythritol
Multi-Targeted Mechanisms Underlying the Endothelial Protective Effects of the Diabetic-Safe Sweetener Erythritol Danie¨lle M. P. H. J. Boesten1*., Alvin Berger2.¤, Peter de Cock3, Hua Dong4, Bruce D. Hammock4, Gertjan J. M. den Hartog1, Aalt Bast1 1 Department of Toxicology, Maastricht University, Maastricht, The Netherlands, 2 Global Food Research, Cargill, Wayzata, Minnesota, United States of America, 3 Cargill RandD Center Europe, Vilvoorde, Belgium, 4 Department of Entomology and UCD Comprehensive Cancer Center, University of California Davis, Davis, California, United States of America Abstract Diabetes is characterized by hyperglycemia and development of vascular pathology. Endothelial cell dysfunction is a starting point for pathogenesis of vascular complications in diabetes. We previously showed the polyol erythritol to be a hydroxyl radical scavenger preventing endothelial cell dysfunction onset in diabetic rats. To unravel mechanisms, other than scavenging of radicals, by which erythritol mediates this protective effect, we evaluated effects of erythritol in endothelial cells exposed to normal (7 mM) and high glucose (30 mM) or diabetic stressors (e.g. SIN-1) using targeted and transcriptomic approaches. This study demonstrates that erythritol (i.e. under non-diabetic conditions) has minimal effects on endothelial cells. However, under hyperglycemic conditions erythritol protected endothelial cells against cell death induced by diabetic stressors (i.e. high glucose and peroxynitrite). Also a number of harmful effects caused by high glucose, e.g. increased nitric oxide release, are reversed. Additionally, total transcriptome analysis indicated that biological processes which are differentially regulated due to high glucose are corrected by erythritol. We conclude that erythritol protects endothelial cells during high glucose conditions via effects on multiple targets. -
Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights Into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle
animals Article Integrating Single-Step GWAS and Bipartite Networks Reconstruction Provides Novel Insights into Yearling Weight and Carcass Traits in Hanwoo Beef Cattle Masoumeh Naserkheil 1 , Abolfazl Bahrami 1 , Deukhwan Lee 2,* and Hossein Mehrban 3 1 Department of Animal Science, University College of Agriculture and Natural Resources, University of Tehran, Karaj 77871-31587, Iran; [email protected] (M.N.); [email protected] (A.B.) 2 Department of Animal Life and Environment Sciences, Hankyong National University, Jungang-ro 327, Anseong-si, Gyeonggi-do 17579, Korea 3 Department of Animal Science, Shahrekord University, Shahrekord 88186-34141, Iran; [email protected] * Correspondence: [email protected]; Tel.: +82-31-670-5091 Received: 25 August 2020; Accepted: 6 October 2020; Published: 9 October 2020 Simple Summary: Hanwoo is an indigenous cattle breed in Korea and popular for meat production owing to its rapid growth and high-quality meat. Its yearling weight and carcass traits (backfat thickness, carcass weight, eye muscle area, and marbling score) are economically important for the selection of young and proven bulls. In recent decades, the advent of high throughput genotyping technologies has made it possible to perform genome-wide association studies (GWAS) for the detection of genomic regions associated with traits of economic interest in different species. In this study, we conducted a weighted single-step genome-wide association study which combines all genotypes, phenotypes and pedigree data in one step (ssGBLUP). It allows for the use of all SNPs simultaneously along with all phenotypes from genotyped and ungenotyped animals. Our results revealed 33 relevant genomic regions related to the traits of interest. -
1 Supporting Information for a Microrna Network Regulates
Supporting Information for A microRNA Network Regulates Expression and Biosynthesis of CFTR and CFTR-ΔF508 Shyam Ramachandrana,b, Philip H. Karpc, Peng Jiangc, Lynda S. Ostedgaardc, Amy E. Walza, John T. Fishere, Shaf Keshavjeeh, Kim A. Lennoxi, Ashley M. Jacobii, Scott D. Rosei, Mark A. Behlkei, Michael J. Welshb,c,d,g, Yi Xingb,c,f, Paul B. McCray Jr.a,b,c Author Affiliations: Department of Pediatricsa, Interdisciplinary Program in Geneticsb, Departments of Internal Medicinec, Molecular Physiology and Biophysicsd, Anatomy and Cell Biologye, Biomedical Engineeringf, Howard Hughes Medical Instituteg, Carver College of Medicine, University of Iowa, Iowa City, IA-52242 Division of Thoracic Surgeryh, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada-M5G 2C4 Integrated DNA Technologiesi, Coralville, IA-52241 To whom correspondence should be addressed: Email: [email protected] (M.J.W.); yi- [email protected] (Y.X.); Email: [email protected] (P.B.M.) This PDF file includes: Materials and Methods References Fig. S1. miR-138 regulates SIN3A in a dose-dependent and site-specific manner. Fig. S2. miR-138 regulates endogenous SIN3A protein expression. Fig. S3. miR-138 regulates endogenous CFTR protein expression in Calu-3 cells. Fig. S4. miR-138 regulates endogenous CFTR protein expression in primary human airway epithelia. Fig. S5. miR-138 regulates CFTR expression in HeLa cells. Fig. S6. miR-138 regulates CFTR expression in HEK293T cells. Fig. S7. HeLa cells exhibit CFTR channel activity. Fig. S8. miR-138 improves CFTR processing. Fig. S9. miR-138 improves CFTR-ΔF508 processing. Fig. S10. SIN3A inhibition yields partial rescue of Cl- transport in CF epithelia. -
2010 Physical Biosciences Research Meeting
2010 Physical Biosciences Research Meeting Sheraton Inner Harbor Hotel Baltimore, MD October 17-20, 2010 Office of Basic Energy Sciences Chemical Sciences, Geosciences & Biosciences Division 2010 Physical Biosciences Research Meeting Program and Abstracts Sheraton Inner Harbor Hotel Baltimore, MD October 17-20, 2010 Chemical Sciences, Geosciences, and Biosciences Division Office of Basic Energy Sciences Office of Science U.S. Department of Energy i Cover art is taken from the public domain and can be found at: http://commons.wikimedia.org/wiki/File:Blue_crab_on_market_in_Piraeus_-_Callinectes_sapidus_Rathbun_20020819- 317.jpg This document was produced under contract number DE-AC05-060R23100 between the U.S. Department of Energy and Oak Ridge Associated Universities. The research grants and contracts described in this document are, unless specifically labeled otherwise, supported by the U.S. DOE Office of Science, Office of Basic Energy Sciences, Chemical Sciences, Geosciences, and Biosciences Division. ii Foreword This volume provides a record of the 2nd biennial meeting of the Principal Investigators (PIs) funded by the Physical Biosciences program, and is sponsored by the Chemical Sciences, Geosciences, and Biosciences Division of the Office of Basic Energy Sciences (BES) in the U.S. Department of Energy (DOE). Within DOE-BES there are two programs that fund basic research in energy-relevant biological sciences, Physical Biosciences and Photosynthetic Systems. These two Biosciences programs, along with a strong program in Solar Photochemistry, comprise the current Photo- and Bio- Chemistry Team. This meeting specifically brings together under one roof all of the PIs funded by the Physical Biosciences program, along with Program Managers and staff not only from DOE-BES, but also other offices within DOE, the national labs, and even other federal funding agencies. -
A Clearer Picture of the ER Translocon Complex Max Gemmer and Friedrich Förster*
© 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs231340. doi:10.1242/jcs.231340 REVIEW A clearer picture of the ER translocon complex Max Gemmer and Friedrich Förster* ABSTRACT et al., 1986). SP-equivalent N-terminal transmembrane helices that The endoplasmic reticulum (ER) translocon complex is the main gate are not cleaved off can also target proteins to the ER through the into the secretory pathway, facilitating the translocation of nascent same mechanism. In this SRP-dependent co-translational ER- peptides into the ER lumen or their integration into the lipid membrane. targeting mode, ribosomes associate with the ER membrane via ER Protein biogenesis in the ER involves additional processes, many of translocon complexes. These membrane protein complexes them occurring co-translationally while the nascent protein resides at translocate nascent soluble proteins into the ER, integrate nascent the translocon complex, including recruitment of ER-targeted membrane proteins into the ER membrane, mediate protein folding ribosome–nascent-chain complexes, glycosylation, signal peptide and membrane protein topogenesis, and modify them chemically. In cleavage, membrane protein topogenesis and folding. To perform addition to co-translational protein import and translocation, distinct such varied functions on a broad range of substrates, the ER ER translocon complexes enable post-translational translocation and translocon complex has different accessory components that membrane integration. This post-translational pathway is widespread associate with it either stably or transiently. Here, we review recent in yeast (Panzner et al., 1995), whereas higher eukaryotes primarily structural and functional insights into this dynamically constituted use it for relatively short peptides (Schlenstedt and Zimmermann, central hub in the ER and its components. -
Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer
ORIGINAL RESEARCH published: 15 April 2021 doi: 10.3389/fonc.2021.566539 Prognostic Significance of Autophagy-Relevant Gene Markers in Colorectal Cancer Qinglian He 1, Ziqi Li 1, Jinbao Yin 1, Yuling Li 2, Yuting Yin 1, Xue Lei 1 and Wei Zhu 1* 1 Department of Pathology, Guangdong Medical University, Dongguan, China, 2 Department of Pathology, Dongguan People’s Hospital, Southern Medical University, Dongguan, China Background: Colorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. However, there is no consensus on the value of autophagy-associated genes in predicting the prognosis of CRC patients. Edited by: This work screens autophagy-related markers and signaling pathways that may Fenglin Liu, Fudan University, China participate in the development of CRC, and establishes a prognostic model of CRC Reviewed by: based on autophagy-associated genes. Brian M. Olson, Emory University, United States Methods: Gene transcripts from the TCGA database and autophagy-associated gene Zhengzhi Zou, data from the GeneCards database were used to obtain expression levels of autophagy- South China Normal University, China associated genes, followed by Wilcox tests to screen for autophagy-related differentially Faqing Tian, Longgang District People's expressed genes. Then, 11 key autophagy-associated genes were identified through Hospital of Shenzhen, China univariate and multivariate Cox proportional hazard regression analysis and used to Yibing Chen, Zhengzhou University, China establish prognostic models. Additionally, immunohistochemical and CRC cell line data Jian Tu, were used to evaluate the results of our three autophagy-associated genes EPHB2, University of South China, China NOL3, and SNAI1 in TCGA. -
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. -
Glycan Engineering for Cell and Developmental Biology
View metadata, citation and similar papers at core.ac.uk brought to you by CORE HHS Public Access provided by Caltech Authors - Main Author manuscript Author ManuscriptAuthor Manuscript Author Cell Chem Manuscript Author Biol. Author Manuscript Author manuscript; available in PMC 2016 May 05. Published in final edited form as: Cell Chem Biol. 2016 January 21; 23(1): 108–121. doi:10.1016/j.chembiol.2015.12.007. Glycan Engineering for Cell and Developmental Biology Matthew E. Griffin1 and Linda C. Hsieh-Wilson1,* 1Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125, USA Abstract Cell-surface glycans are a diverse class of macromolecules that participate in many key biological processes, including cell-cell communication, development, and disease progression. Thus, the ability to modulate the structures of glycans on cell surfaces provides a powerful means not only to understand fundamental processes but also to direct activity and elicit desired cellular responses. Here, we describe methods to sculpt glycans on cell surfaces and highlight recent successes in which artificially engineered glycans have been employed to control biological outcomes such as the immune response and stem cell fate. Introduction Cell-surface glycans participate in many important processes throughout the lifespan of an organism, ranging from cell migration and tissue patterning to the immune response, disease progression, and cell death (Fuster and Esko, 2005; Häcker et al., 2005; Lichtenstein and Rabinovich, 2013; van Kooyk and Rabinovich, 2008). At a molecular level, glycans are often the first points of contact between cells, and they function by facilitating a variety of interactions both in cis (on the same cell) and in trans (on different cells). -
Genetic Editing of SEC61, SEC62, and SEC63 Abrogates Human
bioRxiv preprint doi: https://doi.org/10.1101/653857; this version posted May 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Genetic editing of SEC61, SEC62, and 2 SEC63 abrogates human cytomegalovirus 3 US2 expression in a signal peptide- 4 dependent manner 5 6 7 Anouk B.C. Schuren 1, Ingrid G.J. Boer1, Ellen Bouma1,2, Robert Jan Lebbink1, Emmanuel 8 J.H.J. Wiertz 1,* 9 1Department of Medical Microbiology, University Medical Center Utrecht, 3584CX Utrecht, The Netherlands. 10 2 Current address: Department of Medical Microbiology, University Medical Center Groningen, Postbus 30001, 9700 RB 11 Groningen, The Netherlands 12 *Correspondence: [email protected] (E.J.H.J.W.) 13 14 Abstract 15 Newly translated proteins enter the ER through the SEC61 complex, via either co- or post- 16 translational translocation. In mammalian cells, few substrates of post-translational SEC62- and 17 SEC63-dependent translocation have been described. Here, we targeted all components of the 18 SEC61/62/63 complex by CRISPR/Cas9, creating knock-outs or mutants of the individual subunits of 19 the complex. We show that functionality of the human cytomegalovirus protein US2, which is an 1 bioRxiv preprint doi: https://doi.org/10.1101/653857; this version posted May 29, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.