Interferon-Gamma (IFN-Γ): Exploring Its Implications in Infectious Diseases
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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. -
Duke University Dissertation Template
The Role of Irgm1 in Mitochondrial Dynamics and Metabolism by Elyse Schmidt Department of Molecular Genetics and Microbiology Duke University Date:_______________________ Approved: ___________________________ Gregory Taylor, Supervisor ___________________________ Jörn Coers ___________________________ Tso-Pang Yao ___________________________ Nancie MacIver ___________________________ David Pickup Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Molecular Genetics and Microbiology in the Graduate School of Duke University 2017 i v ABSTRACT The Role of Irgm1 in Mitochondrial Dynamics and Metabolism by Elyse Schmidt Department of Molecular Genetics and Microbiology Duke University Date:_______________________ Approved: ___________________________ Gregory Taylor, Supervisor ___________________________ Jörn Coers ___________________________ Tso-Pang Yao ___________________________ Nancie MacIver ___________________________ David Pickup An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Molecular Genetics and Microbiology in the Graduate School of Duke University 2017 i v Copyright by Elyse Schmidt 2017 Abstract The Immunity-Related GTPases (IRG) are a family of proteins that are induced by interferon (IFN)-γ and play pivotal roles in immune and inflammatory responses. IRGs ostensibly function as dynamin-like proteins that bind to intracellular membranes, and promote remodeling and trafficking of those membranes. Prior studies have shown that loss of Irgm1 in mice leads to increased lethality to bacterial infections, as well as enhanced inflammation to non-infectious stimuli; however, the mechanisms underlying these phenotypes are unclear. In this dissertation, I studied the role of Irgm1 in mitochondrial biology and immunometabolism. Past studies of Irgm1’s human orthologue, IRGM, reported that IRGM localized to mitochondria and induced mitochondrial fragmentation. -
Deficiency in Class III PI3-Kinase Confers Postnatal Lethality with IBD
ARTICLE DOI: 10.1038/s41467-018-05105-8 OPEN Deficiency in class III PI3-kinase confers postnatal lethality with IBD-like features in zebrafish Shaoyang Zhao1,2,3, Jianhong Xia2,3, Xiuhua Wu2,3, Leilei Zhang2,3, Pengtao Wang2,3, Haiyun Wang2,3, Heying Li2, Xiaoshan Wang 2, Yan Chen 2, Jean Agnetti2, Yinxiong Li 2, Duanqing Pei2,3 & Xiaodong Shu2,3 The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phospha- tidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. Here, we report 1234567890():,; that PIK3C3 deficiency in zebrafish results in intestinal injury and inflammation. In pik3c3 mutants, gut tube forms but fails to be maintained. Gene expression analysis reveals that barrier-function-related inflammatory bowel disease (IBD) susceptibility genes (e-cadherin, hnf4a, ttc7a) are suppressed, while inflammatory response genes are stimulated in the mutants. Histological analysis shows neutrophil infiltration into mutant intestinal epithelium and the clearance of gut microbiota. Yet, gut microorganisms appear dispensable as mutants cultured under germ-free condition have similar intestinal defects. Mechanistically, we show that PIK3C3 deficiency suppresses the formation of PI3P and disrupts the polarized dis- tribution of cell-junction proteins in intestinal epithelial cells. These results not only reveal a role of PIK3C3 in gut homeostasis, but also provide a zebrafish IBD model. 1 School of Life Sciences, University of Science and Technology of China, 230027 Hefei, Anhui, China. 2 CAS Key Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health-Guangzhou Medical University Joint School of Biological Sciences, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530 Guangzhou, China. -
Xxviiith Belgian Week of Gastroenterology 2016 All Abstracts Belgian Association for the Study of the Liver (BASL)
XXVIIIth Belgian Week of Gastroenterology 2016 All Abstracts Belgian Association for the Study of the Liver (BASL) A01 Light-to-moderate alcohol intake increases the risk of hepatocellular carcinoma in patients with HCV-related compensated cirrhosis: a prospective study H. VANDENBULCKE (1), C. MORENO (2), I. COLLE (3), J. KNEBEL (4), S. FRANCQUE (5), T. SERSTÉ (6), C. GEORGE (7), C. DE GALOCSY (8), W. LALEMAN (9), J. DELWAIDE (10), H. ORLENT (11), L. LASSER (12), E. TRÉPO (2), H. VAN VLIERBERGHE (3), P. MICHIELSEN (5), M. VAN GOSSUM (6), M. DE VOS (1), A. MAROT (13), C. DOERIG (13), M. ADLER (2), J. HENRION (1), P. DELTENRE (13) / [1] Hôpital de Jolimont, Haine-Saint-Paul, Belgium, Departement of Gastroenterology and Hepatology, [2] Erasme Hospital, Brussels, Belgium, Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, [3] Ghent University, Ghent, Belgium, Departement of Gastroenterology and Hepatology, [4] Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, Division of Radiology, [5] Antwerp University Hospital, Edegem, Belgium, Departement of Gastroenterology and Hepatology, [6] CHU Saint-Pierre, Brussels, Belgium, Departement of Gastroenterology and Hepatology, [7] AZ Groeninge, Kortrijk, Belgium, Departement of Gastroenterology and Hepatology, [8] Hôp. Iris Sud Bracops, Bruxelles, Belgium, Departement of Gastroenterology and Hepatology, [9] KU, Leuven, Belgium, Departement of Gastroenterology and Hepatology, [10] CHU Liege, Liège, Belgium, Departement of Gastroenterology and Hepatology, [11] AZ St. Jan Brugge AV, Brugge, Belgium, Departement of Gastroenterology and Hepatology, [12] CHU Brugmann, , Belgium, Departement of Gastroenterology and Hepatology, [13] Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, Division of Gastroenterology and Hepatology Introduction: Whether light-to-moderate alcohol intake increases the risk of complications in patients with HCV-related cirrhosis remains unclear. -
Ifng-Induced Irgm1 Promotes Tumorigenesis of Melanoma Via Dual Regulation of Apoptosis and Bif-1-Dependent Autophagy
Oncogene (2015) 34, 5363–5371 © 2015 Macmillan Publishers Limited All rights reserved 0950-9232/15 www.nature.com/onc ORIGINAL ARTICLE IFNg-induced Irgm1 promotes tumorigenesis of melanoma via dual regulation of apoptosis and Bif-1-dependent autophagy H Dong1,2,5, L Tian1,5,RLi3,CPei1,YFu1, X Dong1, F Xia1, C Wang1,WLi1, X Guo1,CGu1,BLi1, A Liu4, H Ren1, C Wang2 and H Xu1 Interferon gamma (IFNg) has been known as the regulator for both tumor immune surveillance and tumorgenesis. However, mechanisms underlying the resistance of tumor cell to IFNg have yet been fully understood. In the current study, we showed that immunity-related GTPase family member 1 (mouse: Irgm1; human: IRGM) is essential for IFNg-mediated regulation of tumor cell growth in melanoma. IRGM/Irgm1 was highly expressed in human and mouse melanoma. IFNg and starvation synergistically induced Irgm1 expression in melanoma B16 cells. In vivo, injection of Irgm1-siRNA-treated cells significantly reduced the number of tumor nodules and prolonged the mice survival. In vitro, knockdown endogenous or IFNg-induced Irgm1 significantly decreases the proliferation and increases apoptosis of B16 cells. In addition, suppressing Irgm1 decreased the IFNg/starvation-induced autophagy, while overexpressing Irgm1 significantly increased autophagy and rescued starvation-challenged cells. Moreover, IFNg and starvation-induced the co-localization of Irgm1 with Bax-interacting factor 1 (Bif-1). Knockdown of Bif-1 decreased Irgm1-mediated tumor cell autophagy. Taken together, these data reveal an Irgm1-dependent mechanism that promotes the tumorigenesis of melanoma via dual regulation of apoptosis and Bif-1-dependent autophagy. -
Interplay Between Cellular and Molecular Mechanisms Underlying Inflammatory Bowel Diseases Development—A Focus on Ulcerative Colitis
cells Review Interplay between Cellular and Molecular Mechanisms Underlying Inflammatory Bowel Diseases Development—A Focus on Ulcerative Colitis Iuliana Samoilă 1 , Sorina Dinescu 1,2,* and Marieta Costache 1,2 1 Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania; [email protected] (I.S.); [email protected] (M.C.) 2 Research Institute of the University of Bucharest, 050663 Bucharest, Romania * Correspondence: [email protected] Received: 16 May 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: Inflammatory bowel diseases (IBD) are defined by the continuous inflammation of the gastrointestinal tract. During inflammation, the number of pathogens in the intestinal epithelium increases, leading to inflammasome assembly. Inflammasome activation is meant to protect the intestinal epithelial barrier from further damage by maintaining homeostasis. Although its purpose is to protect the cells, excessive nucleotide-binding oligomerization domain-like receptor and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly is responsible for the synthesis of a high number of pro-inflammatory cytokines. The activation of two crucial pathways, autophagy process, and unfolded protein response, is initiated for restoring homeostasis. Aberrant expression of miRNAs and lncRNAs also interfere with the pathogenic mechanisms of IBD, as these non-coding transcripts play key roles in regulation of biological processes, such as inflammation and immunity. This review thoroughly describes the cellular and molecular mechanism that trigger and perpetuate inflammation in ulcerative colitis (UC) patients. Keywords: inflammasome; NLRP3; autophagy; miRNAs in IBD; inflammatory bowel diseases 1. Introduction Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the gastrointestinal tract, with alternating phases of clinical relapse and remission [1]. -
Exposing Toxoplasma Gondii Hiding Inside the Vacuole: a Role for Gbps, Autophagy and Host Cell Death
HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Curr Opin Manuscript Author Microbiol. Author Manuscript Author manuscript; available in PMC 2020 February 06. Published in final edited form as: Curr Opin Microbiol. 2017 December ; 40: 72–80. doi:10.1016/j.mib.2017.10.021. Exposing Toxoplasma gondii hiding inside the vacuole: a role for GBPs, autophagy and host cell death Jeroen P Saeij1, Eva-Maria Frickel2 1School of Veterinary Medicine, Department of Pathology, Microbiology and Immunology, University of California, Davis, Davis, CA 95616, USA 2The Francis Crick Institute, Host-Toxoplasma Interaction Laboratory, 1 Midland Road, London NW1 1AT, UK Abstract The intracellular parasite Toxoplasma gondii resides inside a vacuole, which shields it from the host’s intracellular defense mechanisms. The cytokine interferon gamma (IFNγ) upregulates host cell effector pathways that are able to destroy the vacuole, restrict parasite growth and induce host cell death. Interferon-inducible GTPases such as the Guanylate Binding Proteins (GBPs), autophagy proteins and ubiquitin-driven mechanisms play important roles in Toxoplasma control in mice and partly also in humans. The host inflammasome is regulated by GBPs in response to bacterial infection in murine cells and may also respond to Toxoplasma infection. Elucidation of murine Toxoplasma defense mechanisms are guiding studies on human cells, while inevitably leading to the discovery of human-specific pathways that often function in a cell type-dependent manner. Introduction Toxoplasma gondii is an important pathogen of animals and humans with ~30% of the world’s population chronically infected. While immunocompetent people generally control the infection, Toxoplasma infection can lead to congenital abnormalities, ocular disease and health problems in the immunocompromised. -
An Overview on ERAP Roles in Infectious Diseases
cells Review An Overview on ERAP Roles in Infectious Diseases 1,2, , 1, 2,3 1 Irma Saulle * y, Chiara Vicentini y, Mario Clerici and Mara Biasin 1 Cattedra di Immunologia, Dipartimento di Scienze Biomediche e Cliniche L. Sacco”, Università degli Studi di Milano, 20157 Milan, Italy; [email protected] (C.V.); [email protected] (M.B.) 2 Cattedra di Immunologia, Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti Università degli Studi di Milano, 20122 Milan, Italy; [email protected] 3 IRCCS Fondazione Don Carlo Gnocchi, 20157 Milan, Italy * Correspondence: [email protected]; Tel.: +39-0250319679 These authors equally contributed to this work. y Received: 13 February 2020; Accepted: 12 March 2020; Published: 14 March 2020 Abstract: Endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 (ERAPs) are crucial enzymes shaping the major histocompatibility complex I (MHC I) immunopeptidome. In the ER, these enzymes cooperate in trimming the N-terminal residues from precursors peptides, so as to generate optimal-length antigens to fit into the MHC class I groove. Alteration or loss of ERAPs function significantly modify the repertoire of antigens presented by MHC I molecules, severely affecting the activation of both NK and CD8+ T cells. It is, therefore, conceivable that variations affecting the presentation of pathogen-derived antigens might result in an inadequate immune response and onset of disease. After the first evidence showing that ERAP1-deficient mice are not able to control Toxoplasma gondii infection, a number of studies have demonstrated that ERAPs are control factors for several infectious organisms. In this review we describe how susceptibility, development, and progression of some infectious diseases may be affected by different ERAPs variants, whose mechanism of action could be exploited for the setting of specific therapeutic approaches. -
Influence of ERAP1 and ERAP2 Gene Polymorphisms on Disease
Human Immunology 80 (2019) 325–334 Contents lists available at ScienceDirect Human Immunology journal homepage: www.elsevier.com/locate/humimm Influence of ERAP1 and ERAP2 gene polymorphisms on disease T susceptibility in different populations ⁎ Yufeng Yaoa,b, Nannan Liua, Ziyun Zhoua, Li Shia,b, a Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China b Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, Kunming 650118, China ARTICLE INFO ABSTRACT Keywords: The endoplasmic reticulum aminopeptidases (ERAPs), ERAP1 and ERAP2, makes a role in shaping the HLA class ERAP1 I peptidome by trimming peptides to the optimal size in MHC-class I-mediated antigen presentation and edu- ERAP2 cating the immune system to differentiate between self-derived and foreign antigens. Association studies have Polymorphism shown that genetic variations in ERAP1 and ERAP2 genes increase susceptibility to autoimmune diseases, in- Disease association fectious diseases, and cancers. Both ERAP1 and ERAP2 genes exhibit diverse polymorphisms in different po- Population genetic background pulations, which may influence their susceptibly to the aforementioned diseases. In this article, we reviewthe distribution of ERAP1 and ERAP2 gene polymorphisms in various populations; discuss the risk or protective influence of these gene polymorphisms in autoimmune diseases, infectious diseases, and cancers; and highlight how ERAP genetic variations can influence disease associations. 1. ERAP gene introduction to CD8+ T cells [1,2]. ERAPs have been found to trim peptides to the optimal size for MHC-I binding [3,4] but can also over-trim and destroy 1.1. ERAPs play an important role in the antigen presentation process MHC-I ligands. -
Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-Cov-2 Infection: What Can Be Learned from Other Coronaviruses
International Journal of Molecular Sciences Review Autophagy, Unfolded Protein Response, and Neuropilin-1 Cross-Talk in SARS-CoV-2 Infection: What Can Be Learned from Other Coronaviruses Morvarid Siri 1 , Sanaz Dastghaib 2 , Mozhdeh Zamani 1 , Nasim Rahmani-Kukia 3 , Kiarash Roustai Geraylow 4 , Shima Fakher 3, Fatemeh Keshvarzi 3, Parvaneh Mehrbod 5 , Mazaher Ahmadi 6 , Pooneh Mokarram 1,3,* , Kevin M. Coombs 7 and Saeid Ghavami 1,8,9,* 1 Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran; [email protected] (M.S.); [email protected] (M.Z.) 2 Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz 7193635899, Iran; [email protected] 3 Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz 7134845794, Iran; [email protected] (N.R.-K.); [email protected] (S.F.); [email protected] (F.K.) 4 Student Research Committee, Semnan University of Medical Sciences, Semnan 3514799422, Iran; [email protected] 5 Influenza and Respiratory Viruses Department, Pasteur Institute of Iran, Tehran 1316943551, Iran; [email protected] 6 Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838695, Iran; [email protected] 7 Department of Medical Microbiology and Infectious Diseases, Rady Faculty of Health Sciences, Max Rady Citation: Siri, M.; Dastghaib, S.; College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada; [email protected] Zamani, M.; Rahmani-Kukia, N.; 8 Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College Geraylow, K.R.; Fakher, S.; Keshvarzi, of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada F.; Mehrbod, P.; Ahmadi, M.; 9 Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland Mokarram, P.; et al. -
Sex-Specific Differences in Endoplasmic Reticulum Aminopeptidase 1 Modulation Influence Blood Pressure and Renin-Angiotensin System Responses
Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin-angiotensin system responses Sanjay Ranjit, … , Gordon H. Williams, Jose R. Romero JCI Insight. 2019;4(21):e129615. https://doi.org/10.1172/jci.insight.129615. Research Article Endocrinology Salt sensitivity of blood pressure (SSBP) and hypertension are common, but the underlying mechanisms remain unclear. Endoplasmic reticulum aminopeptidase 1 (ERAP1) degrades angiotensin II (ANGII). We hypothesized that decreasing ERAP1 increases BP via ANGII-mediated effects on aldosterone (ALDO) production and/or renovascular function. Compared with WT littermate mice, ERAP1-deficient (ERAP1+/–) mice had increased tissue ANGII, systolic and diastolic BP, and SSBP, indicating that ERAP1 deficiency leads to volume expansion. However, the mechanisms underlying the volume expansion differed according to sex. Male ERAP1+/– mice had increased ALDO levels and normal renovascular responses to volume expansion (decreased resistive and pulsatility indices and increased glomerular volume). In contrast, female ERAP1+/– mice had normal ALDO levels but lacked normal renovascular responses. In humans,E RAP1 rs30187, a loss-of-function gene variant that reduces ANGII degradation in vitro, is associated with hypertension. In our cohort from the Hypertensive Pathotype (HyperPATH) Consortium, there was a significant dose-response association between rs30187 risk alleles and systolic and diastolic BP as well as renal plasma flow in men, but not in women. Thus, lowering ERAP1 led to volume expansion and increased BP. In males, the volume expansion was due to elevated ALDO with normal renovascular function, whereas in females the volume expansion was due to impaired renovascular function with normal ALDO levels. Find the latest version: https://jci.me/129615/pdf RESEARCH ARTICLE Sex-specific differences in endoplasmic reticulum aminopeptidase 1 modulation influence blood pressure and renin- angiotensin system responses Sanjay Ranjit, Jian Yao Wong, Jia W. -
Supp Table 6.Pdf
Supplementary Table 6. Processes associated to the 2037 SCL candidate target genes ID Symbol Entrez Gene Name Process NM_178114 AMIGO2 adhesion molecule with Ig-like domain 2 adhesion NM_033474 ARVCF armadillo repeat gene deletes in velocardiofacial syndrome adhesion NM_027060 BTBD9 BTB (POZ) domain containing 9 adhesion NM_001039149 CD226 CD226 molecule adhesion NM_010581 CD47 CD47 molecule adhesion NM_023370 CDH23 cadherin-like 23 adhesion NM_207298 CERCAM cerebral endothelial cell adhesion molecule adhesion NM_021719 CLDN15 claudin 15 adhesion NM_009902 CLDN3 claudin 3 adhesion NM_008779 CNTN3 contactin 3 (plasmacytoma associated) adhesion NM_015734 COL5A1 collagen, type V, alpha 1 adhesion NM_007803 CTTN cortactin adhesion NM_009142 CX3CL1 chemokine (C-X3-C motif) ligand 1 adhesion NM_031174 DSCAM Down syndrome cell adhesion molecule adhesion NM_145158 EMILIN2 elastin microfibril interfacer 2 adhesion NM_001081286 FAT1 FAT tumor suppressor homolog 1 (Drosophila) adhesion NM_001080814 FAT3 FAT tumor suppressor homolog 3 (Drosophila) adhesion NM_153795 FERMT3 fermitin family homolog 3 (Drosophila) adhesion NM_010494 ICAM2 intercellular adhesion molecule 2 adhesion NM_023892 ICAM4 (includes EG:3386) intercellular adhesion molecule 4 (Landsteiner-Wiener blood group)adhesion NM_001001979 MEGF10 multiple EGF-like-domains 10 adhesion NM_172522 MEGF11 multiple EGF-like-domains 11 adhesion NM_010739 MUC13 mucin 13, cell surface associated adhesion NM_013610 NINJ1 ninjurin 1 adhesion NM_016718 NINJ2 ninjurin 2 adhesion NM_172932 NLGN3 neuroligin