DOCSLIB.ORG

A20 (Tnfaip3) Is a Negative Feedback Regulator of RIG-I-Mediated IFN Induction in Teleost T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A20 (Tnfaip3) Is a Negative Feedback Regulator of RIG-I-Mediated IFN Induction in Teleost T Fish and Shellfish Immunology 84 (2019) 857–864 Contents lists available at ScienceDirect Fish and Shellfish Immunology journal homepage: www.elsevier.com/locate/fsi Full length article A20 (tnfaip3) is a negative feedback regulator of RIG-I-Mediated IFN induction in teleost T Emilie Mérour, Raphaël Jami, Annie Lamoureux, Julie Bernard, Michel Brémont, ∗ Stéphane Biacchesi VIM, INRA, Université Paris-Saclay, 78350, Jouy-en-Josas, France ARTICLE INFO ABSTRACT Keywords: Interferon production is tightly regulated in order to prevent excessive immune responses. The RIG-I signaling A20 pathway, which is one of the major pathways inducing the production of interferon, is therefore finely regulated TNFAIP3 through the participation of different molecules such as A20 (TNFAIP3). A20 is a negative key regulatory factor RIG-I of the immune response. Although A20 has been identified and actively studied in mammals, nothing is known Interferon about its putative function in lower vertebrates. In this study, we sought to define the involvement of fish A20 Teleost orthologs in the regulation of RIG-I signaling. We showed that A20 completely blocked the activation of IFN and ISG promoters mediated by RIG-I. Furthermore, A20 expression in fish cells was sufficient to reverse the antiviral state induced by the expression of a constitutively active form of RIG-I, thus allowing the efficient replication of a fish rhabdovirus, the viral hemorrhagic septicemia virus (VHSV). We brought evidence that A20 interrupted RIG-I signaling at the level of TBK1 kinase, a critical point of convergence for many different pathways that activates important transcription factors involved in the expression of many cytokines. Finally, we showed that A20 expression was directly induced by the RIG-I pathway demonstrating that fish A20 acts as a negative feedback regulator of this key pathway for the establishment of an antiviral state. 1. Introduction cytokines. Both TANK-binding kinase 1 (TBK1) and inhibitor-κB kinase ε (IKKε) protein kinases phosphorylate IRF3/IRF7, although TBK1 The innate immune response against virus infection is characterized seems to be the main kinase involved in IRF3/IRF7 activation [3–5]. by the induction of a rapid non-specific antiviral state in order to block Given the critical role of the RIG-I-mediated IFN induction pathway virus replication and spread. This primary immune response involves a and to avoid extensive tissue damage upon resolution of infection, ne- large panel of different pattern recognition receptors (PRRs), including gative regulatory loops are essential to maintain the immune homeo- TLRs and RIG-I-like receptors (RLRs), able to detect distinct viral mo- static balance and to ensure the proper termination of the antiviral lecular patterns, such as nucleic acids and viral proteins, collectively response [6,7]. Among a long list of molecules, the NF-κB dependent known as pathogen-associated molecular patterns (PAMPs). PRR acti- gene, A20, also known as tumor necrosis factor alpha-induced protein 3 vation triggers multiple signaling cascades that lead to the induction of or TNFAIP3 [8], has emerged as a key player in the termination of type I interferons (IFNs) which establish the antiviral state and stimu- tumor necrosis factor (TNF)-induced apoptosis [9], the negative feed- late the adaptive immune response [1]. Among the PRRs, RLRs play a back regulation of inflammation mediated by NF-κB[10,11], and the key role in sensing viral nucleic acids in the cell cytosol and are es- negative control of the IFN pathway by preventing prolonged IRF3 sential in the early induction of type I IFN [2]. Upon viral RNA detec- activation and IFN overexpression following viral infection [12,13]. tion, RIG-I-like receptors reconform and interact with the mitochon- A20 is a cytoplasmic protein of 90 kDa that is expressed in most cell drial activator of virus signaling (MAVS) protein, also known as IPS-1, types and with dual catalytic activity. A20 is an ubiquitin-editing pro- VISA or Cardif. This interaction induces the recruitment of numerous tein with a deubiquitinase activity mediated by its ovarian tumor (OTU) adaptor proteins and kinases to activate IRF3/IRF7 and NF-κB tran- domain at the N-terminal and a C-terminal domain characterized by a scription factors which then translocate from the cytosol to the nucleus seven zinc finger (ZF) structure functioning as an E3 ubiquitin ligase. and induce the expression of the type I IFNs and inflammatory A20 catalyzes the K48-linked ubiquitylation of target proteins through ∗ Corresponding author. E-mail address: [email protected] (S. Biacchesi). https://doi.org/10.1016/j.fsi.2018.10.082 Received 30 August 2018; Received in revised form 1 October 2018; Accepted 29 October 2018 Available online 30 October 2018 1050-4648/ © 2018 Elsevier Ltd. All rights reserved. E. Mérour et al. Fish and Shellfish Immunology 84 (2019) 857–864 its C-terminal ZF domain, a signal for proteasomal degradation. In salmon TO cells were extracted using RNeasy kit (QIAGEN) according parallel, A20 removes K63-linked ubiquitin chains, which function as to the manufacturer's instructions. The RNA was used to generate full- docking sites for protein-protein interactions, from its target proteins length cDNAs using the SMART RACE cDNA amplification kit (BD through its N-terminal OTU domain. The removal of K63-linked ubi- Clontech) with universal primers provided by the manufacturer. PCR quitin chains inactivates the signaling function of the target proteins amplifications were performed using the Advantage 2 PCR kit (BD and facilitates its K48-linked ubiquitylation and degradation [11]. Clontech) by following the instructions recommended by the manu- A20 has been demonstrated as an important negative regulator of facturer for the PCR reaction mixture and the amplification conditions RIG-I signaling [14]. In response to viral infection, RIG-I-like receptors and with gene-specific primers (Table S1A) designed from the ESTs (RIG-I/MDA5) recognize viral RNA and trigger the downstream cascade sequences found in GenBank. The overall nucleotide identities of the through the mitochondrial adaptor MAVS and the E3 ubiquitin ligase sequences between zebrafish and fathead minnow and zebrafish and TRAF3. TRAF3 mediates K63-linked polyubiquitinations of some TBK1 salmon were 83% and 73%, respectively. RT-PCR products were pur- lysine residues, a post-translational modification required for TBK1 ified with QIAquick PCR purification kit (QIAGEN), cloned into the activation by trans-autophosphorylation [15]. As a critical kinase in- eukaryotic expression vectors pcDNA1.1/Amp (Invitrogen), modified to volved in IFN expression, the activity of TBK1 must be tightly regulated fused an HA tag at the 5′ end of the gene of interest, and fully se- [7]. The A20 regulatory complex, including tax1-binding protein 1 quenced. The Neighbor-joining (NJ) phylogenetic tree of A20 was cal- (TAX1BP1) and A20 binding inhibitor of NF-κB 1 (ABIN1) in associa- culated by MEGA6 software [22] based on a multiple alignment (using tion with A20, antagonizes K63-linked polyubiquitination of TBK1 by ClustalW) of full-length A20 amino-acid sequences from fish and other disrupting the interaction between TBK1 and TRAF3 [16,17]. However, vertebrates (protein accession numbers Table S2) and a 1000-boostrap it is still unclear whether the inhibitory effect on IRF3/IRF7 is direct, was performed. through A20 binding to TBK1 and decrease of TBK1 kinase activity, and/or indirect through A20 recruitment to the adaptor molecule 2.3. Transfection, fluorescence microscopy and luciferase activity assay TAX1BP1, where it cooperates with ABIN1 to inhibit TBK1 activation [14]. EPC cells were plated into 6-well plates at a density of 5 × 106 cells The IFN system is remarkably conserved in vertebrates. In parti- per well 24 h prior to transfection by electroporation (Amaxa cular, teleost fish possess functional RLR pathway whose induction by Biosystems; Lonza) as previously described [23]. At 24 or 48 h post- viral pathogens leads to the induction of type I interferon. Several transfection, cells were fixed or lysed for further experiments. Plasmids groups showed that fish have orthologs of human RLRs, including RIG- constructs used in the present study were previously described (RIG-I I, MDA5 and LGP2, as well as several downstream signaling molecules, Nter-eGFP, MAVS, eGFP-MAVS, TBK1, 3xFlag-TBK1, PPM1Bb and such as MAVS, TBK1/IKKε and IRF3/IRF7 [18,19]. To date, almost IRF3ΔCter) [23–25]. nothing is known about the fine regulation of the RIG-I-mediated IFN For immunofluorescence microscopy, the cell monolayers were expression [20]. In the present study, we sought to define the in- fixed with a mixture of alcohol and acetone [1:1 (v/v)] or with 80% volvement of fish A20 orthologs in the regulation of RIG-I signaling. methanol, after mitochondria staining using 500 nM of MitoTracker Activation of IFN or ISG promoters by RIG-I was completely inhibited DeepRed FM (Invitrogen) at −20 °C for 15 min. Antigen detection was by A20 expression in fish cells. We showed that A20 interrupted RIG-I performed by incubation with mouse anti-Flag M2 (1/200) or rabbit signaling at the level of TBK1 by physically interacting and co-loca- anti-HA mAbs (1/50; Sigma) diluted in 1x PBS containing 0.05% Tween lizing with this important kinase. Furthermore, fish cells expressing the 20 for 45 min at room temperature. Cells were then washed three times, active form of RIG-I induced an antiviral state that totally blocked re- incubated with Alexa Fluor 488-conjugated anti-mouse and Alexa Fluor plication of a Piscine Novirhabdovirus, the viral hemorrhagic septicemia 594-conjugated anti-rabbit immunoglobulins (Invitrogen) for 45 min at virus (VHSV), an effect that was reversed by co-expression of A20. Fi- room temperature and washed again. Cell monolayers were then vi- nally, we showed that A20 was up-regulated by the RIG-I pathway itself sualized directly with a UV-light microscope (Carl Zeiss) after mounting demonstrating that fish A20 acts as a negative feedback regulator of of the coverslips using Pro-Long Gold antifade reagent with 4’, 6-dia- RIG-I-mediated induction of the antiviral state.
Load more

Recommended publications
  • 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.
    [Show full text]
  • Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1
    Research Article Human T-Cell Leukemia Virus Oncoprotein Tax Represses Nuclear Receptor–Dependent Transcription by Targeting Coactivator TAX1BP1 King-Tung Chin,1 Abel C.S. Chun,1 Yick-Pang Ching,1,2 Kuan-Teh Jeang,3 and Dong-Yan Jin1 Departments of 1Biochemistry and 2Pathology, The University of Hong Kong, Pokfulam, Hong Kong and 3Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland Abstract studied. Accordingly, we understand that Tax functions as a Human T-cell leukemia virus type 1 oncoprotein Tax is a homodimer (12, 13), which docks with dimeric CREB in a ternary transcriptional regulator that interacts with a large number of complex onto the HTLV-1 21-bp TRE motifs (14). Optimal activa- host cell factors. Here, we report the novel characterization of tion of the HTLV-1 LTR by Tax requires the core HTLV-1 TATAA promoter, CREB, and the TRE (15). Separately, Tax activation of the interaction of Tax with a human cell protein named Tax1- n binding protein 1 (TAX1BP1). We show that TAX1BP1 is a NF- B is thought to occur through direct interaction with p50/p52, n n g g nuclear receptor coactivator that forms a complex with the I B, and I B kinase (IKK ; ref. 3). Moreover, Tax can also engage glucocorticoid receptor. TAX1BP1 and Tax colocalize into transcriptional coactivators such as CREB-binding protein (CBP), p300, P/CAF, and TORC1/2/3 (16–18). intranuclear speckles that partially overlap with but are not identical to the PML oncogenic domains. Tax binds TAX1BP1 Although we know much about how Tax activates transcription, directly, induces the dissociation of TAX1BP1 from the we know considerably less about how it represses gene expression.
    [Show full text]
  • Depletion of TAX1BP1 Amplifies Innate Immune Responses During Respiratory
    bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.447014; this version posted June 7, 2021. 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 Depletion of TAX1BP1 amplifies innate immune responses during respiratory 2 syncytial virus infection 3 4 Running title: Revealing the role of TAX1BP1 during RSV infection 5 6 Delphyne Descamps1*, Andressa Peres de Oliveira2, Lorène Gonnin1, Sarah Madrières1, Jenna Fix1, 7 Carole Drajac1, Quentin Marquant1, Edwige Bouguyon1, Vincent Pietralunga1, Hidekatsu Iha4, 8 Armando Morais Ventura2, Frédéric Tangy3, Pierre-Olivier Vidalain3,5, Jean-François Eléouët1, and 9 Marie Galloux1* 10 11 1 Université Paris-Saclay, INRAE, UVSQ, VIM, 78350, Jouy-en-Josas, France. 12 2 Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São 13 Paulo, Brazil 14 3 Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR-3569, 75015 Paris, France. 15 4 Department of Infectious Diseases, Faculty of Medicine, Oita University Idaiga-oka, Hasama Yufu, 16 Japan 17 5 CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université 18 Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France. 19 20 * Correspondence: [email protected] and [email protected] 21 22 Keywords: RSV, TAX1BP1, nucleoprotein, innate immunity, interferons, lung, yeast two-hydrid 23 screening 24 25 26 27 28 29 30 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.03.447014; this version posted June 7, 2021.
    [Show full text]
  • Identification of Differentially Expressed Genes in Human Bladder Cancer Through Genome-Wide Gene Expression Profiling
    521-531 24/7/06 18:28 Page 521 ONCOLOGY REPORTS 16: 521-531, 2006 521 Identification of differentially expressed genes in human bladder cancer through genome-wide gene expression profiling KAZUMORI KAWAKAMI1,3, HIDEKI ENOKIDA1, TOKUSHI TACHIWADA1, TAKENARI GOTANDA1, KENGO TSUNEYOSHI1, HIROYUKI KUBO1, KENRYU NISHIYAMA1, MASAKI TAKIGUCHI2, MASAYUKI NAKAGAWA1 and NAOHIKO SEKI3 1Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520; Departments of 2Biochemistry and Genetics, and 3Functional Genomics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan Received February 15, 2006; Accepted April 27, 2006 Abstract. Large-scale gene expression profiling is an effective CKS2 gene not only as a potential biomarker for diagnosing, strategy for understanding the progression of bladder cancer but also for staging human BC. This is the first report (BC). The aim of this study was to identify genes that are demonstrating that CKS2 expression is strongly correlated expressed differently in the course of BC progression and to with the progression of human BC. establish new biomarkers for BC. Specimens from 21 patients with pathologically confirmed superficial (n=10) or Introduction invasive (n=11) BC and 4 normal bladder samples were studied; samples from 14 of the 21 BC samples were subjected Bladder cancer (BC) is among the 5 most common to microarray analysis. The validity of the microarray results malignancies worldwide, and the 2nd most common tumor of was verified by real-time RT-PCR. Of the 136 up-regulated the genitourinary tract and the 2nd most common cause of genes we detected, 21 were present in all 14 BCs examined death in patients with cancer of the urinary tract (1-7).
    [Show full text]
  • Role and Mechanisms of Mitophagy in Liver Diseases
    cells Review Role and Mechanisms of Mitophagy in Liver Diseases Xiaowen Ma 1, Tara McKeen 1, Jianhua Zhang 2 and Wen-Xing Ding 1,* 1 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; [email protected] (X.M.); [email protected] (T.M.) 2 Department of Pathology, Division of Molecular Cellular Pathology, University of Alabama at Birmingham, 901 19th street South, Birmingham, AL 35294, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-913-588-9813 Received: 13 February 2020; Accepted: 28 March 2020; Published: 31 March 2020 Abstract: The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases. Keywords: alcohol; autophagy; mitochondria; NAFLD; Parkin; Pink1 1. Introduction Autophagy (or macroautophagy) involves the formation of a double membrane structure called an autophagosome. Autophagosomes bring the enveloped cargoes to the lysosomes to form autolysosomes where the lysosomal enzymes consequently degrade the cargos [1,2].
    [Show full text]
  • Mechanistic Insights Into the Interactions of NAP1 with the SKICH Domains of NDP52 and TAX1BP1
    Mechanistic insights into the interactions of NAP1 with the SKICH domains of NDP52 and TAX1BP1 Tao Fua, Jianping Liua, Yingli Wanga, Xingqiao Xiea, Shichen Hua, and Lifeng Pana,1 aState Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200032 Shanghai, China Edited by Beth Levine, The University of Texas Southwestern, Dallas, TX, and approved October 30, 2018 (received for review July 3, 2018) NDP52 and TAX1BP1, two SKIP carboxyl homology (SKICH) domain- enterica Typhimurium, and the depolarized mitochondria (mitoph- containing autophagy receptors, play crucial roles in selective agy) (15–18). In addition, NDP52 was reported to mediate selective autophagy. The autophagic functions of NDP52 and TAX1BP1 are autophagic degradations of retrotransposon RNA (19) and specific regulated by TANK-binding kinase 1 (TBK1), which may associate functional proteins, including DICER and AGO2 in the miRNA with them through the adaptor NAP1. However, the molecular pathway and MAVS in immune signaling (20, 21). Notably, genetic mechanism governing the interactions of NAP1 with NDP52 and mutation of NDP52 is directly linked to Crohn’s disease, a type of TAX1BP1, as well as the effects induced by TBK1-mediated phos- inflammatory bowel disease likely caused by a combination of en- phorylation of NDP52 and TAX1BP1, remains elusive. Here, we vironmental, immune, and bacterial factors (22). Except for the report the atomic structures of the SKICH regions of NDP52 and diverse central coiled-coil region, NDP52 and TAX1BP1 share a TAX1BP1 in complex with NAP1, which not only uncover the mech- highly similar domain structure (Fig.
    [Show full text]
  • Downregulation of A20 Expression Increases the Immune Response and Apoptosis and Reduces Virus Production in Cells Infected by the Human Respiratory Syncytial Virus
    Article Downregulation of A20 Expression Increases the Immune Response and Apoptosis and Reduces Virus Production in Cells Infected by the Human Respiratory Syncytial Virus María Martín-Vicente 1 , Rubén González-Sanz 1, Isabel Cuesta 2, Sara Monzón 2, 1, 1, Salvador Resino y and Isidoro Martínez * 1 Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; [email protected] (M.M.-V.); [email protected] (R.G.-S.); [email protected] (S.R.) 2 Unidad de Bioinformática, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain; [email protected] (I.C.); [email protected] (S.M.) * Correspondence: [email protected]; Tel.: +34-91-8223272; Fax: +34-91-5097919 Alternative correspondence: [email protected]; Tel.: +34-91-822-3266; Fax: +34-91-509-7919. y Received: 8 January 2020; Accepted: 19 February 2020; Published: 24 February 2020 Abstract: Human respiratory syncytial virus (HRSV) causes severe lower respiratory tract infections in infants, the elderly, and immunocompromised adults. Regulation of the immune response against HRSV is crucial to limiting virus replication and immunopathology. The A20/TNFAIP3 protein is a negative regulator of nuclear factor kappa B (NF-κB) and interferon regulatory factors 3/7 (IRF3/7), which are key transcription factors involved in the inflammatory/antiviral response of epithelial cells to virus infection. Here, we investigated the impact of A20 downregulation or knockout on HRSV growth and the induction of the immune response in those cells. Cellular infections in which the expression of A20 was silenced by siRNAs or eliminated by gene knockout showed increased inflammatory/antiviral response and reduced virus production.
    [Show full text]
  • Array Painting Reveals a High Frequency of Balanced Translocations in Breast Cancer Cell Lines That Break in Cancer-Relevant Genes
    Oncogene (2008) 27, 3345–3359 & 2008 Nature Publishing Group All rights reserved 0950-9232/08 $30.00 www.nature.com/onc ONCOGENOMICS Array painting reveals a high frequency of balanced translocations in breast cancer cell lines that break in cancer-relevant genes KD Howarth1, KA Blood1,BLNg2, JC Beavis1, Y Chua1, SL Cooke1, S Raby1, K Ichimura3, VP Collins3, NP Carter2 and PAW Edwards1 1Department of Pathology, Hutchison-MRC Research Centre, University of Cambridge, Cambridge, UK; 2Wellcome Trust Sanger Institute, Cambridge, UK and 3Department of Pathology, Division of Molecular Histopathology, Addenbrookes Hospital, University of Cambridge, Cambridge, UK Chromosome translocations in the common epithelial tion and inversion, which can result in gene fusion, cancers are abundant, yet little is known about them. promoter insertion or gene inactivation. As is well They have been thought to be almost all unbalanced and known in haematopoietic tumours and sarcomas, therefore dismissed as mostly mediating tumour suppres- translocations and inversions can have powerful onco- sor loss. We present a comprehensive analysis by array genic effects on specific genes and play a central role in painting of the chromosome translocations of breast cancer development (Rowley, 1998). In the past there cancer cell lines HCC1806, HCC1187 and ZR-75-30. In has been an implicit assumption that such rearrange- array painting, chromosomes are isolated by flow ments are not significant players in the common cytometry, amplified and hybridized to DNA microarrays. epithelial
    [Show full text]
  • Oligomerization of Selective Autophagy Receptors for the Targeting and Degradation of Protein Aggregates
    cells Review Oligomerization of Selective Autophagy Receptors for the Targeting and Degradation of Protein Aggregates Wenjun Chen 1,2, Tianyun Shen 1, Lijun Wang 1 and Kefeng Lu 1,* 1 Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; [email protected] (W.C.); [email protected] (T.S.); [email protected] (L.W.) 2 Department of Neurology, Shanxi Provincial People’s Hospital, Taiyuan 030012, China * Correspondence: [email protected] Abstract: The selective targeting and disposal of solid protein aggregates are essential for cells to maintain protein homoeostasis. Autophagy receptors including p62, NBR1, Cue5/TOLLIP (CUET), and Tax1-binding protein 1 (TAX1BP1) proteins function in selective autophagy by targeting ubiq- uitinated aggregates through ubiquitin-binding domains. Here, we summarize previous beliefs and recent findings on selective receptors in aggregate autophagy. Since there are many reviews on selective autophagy receptors, we focus on their oligomerization, which enables receptors to function as pathway determinants and promotes phase separation. Keywords: receptors; autophagy; proteasome; ubiquitin; p62; Dsk2; Cue5; TAX1BP1 1. Introduction Citation: Chen, W.; Shen, T.; Wang, Protein misfolding and the subsequent aggregation caused by various stressors can L.; Lu, K. Oligomerization of Selective be cytotoxic to cells and may lead to cell death. To maintain cellular homeostasis, organ- Autophagy Receptors for the isms use various protein quality-control pathways to either repair misfolded proteins or Targeting and Degradation of Protein target them for degradation if misfolding or aggregation persists [1,2]. In general, pro- Aggregates. Cells 2021, 10, 1989. tein substrates with different statuses, soluble or aggregated, are targeted and degraded https://doi.org/10.3390/cells10081989 by proteasome and autophagy pathways, respectively [3].
    [Show full text]
  • Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors
    University of Cincinnati Date: 12/20/2010 I, Arturo R Maldonado , hereby submit this original work as part of the requirements for the degree of Doctor of Philosophy in Developmental Biology. It is entitled: Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors Student's name: Arturo R Maldonado This work and its defense approved by: Committee chair: Jeffrey Whitsett Committee member: Timothy Crombleholme, MD Committee member: Dan Wiginton, PhD Committee member: Rhonda Cardin, PhD Committee member: Tim Cripe 1297 Last Printed:1/11/2011 Document Of Defense Form Molecular Targeting and Enhancing Anticancer Efficacy of Oncolytic HSV-1 to Midkine Expressing Tumors A dissertation submitted to the Graduate School of the University of Cincinnati College of Medicine in partial fulfillment of the requirements for the degree of DOCTORATE OF PHILOSOPHY (PH.D.) in the Division of Molecular & Developmental Biology 2010 By Arturo Rafael Maldonado B.A., University of Miami, Coral Gables, Florida June 1993 M.D., New Jersey Medical School, Newark, New Jersey June 1999 Committee Chair: Jeffrey A. Whitsett, M.D. Advisor: Timothy M. Crombleholme, M.D. Timothy P. Cripe, M.D. Ph.D. Dan Wiginton, Ph.D. Rhonda D. Cardin, Ph.D. ABSTRACT Since 1999, cancer has surpassed heart disease as the number one cause of death in the US for people under the age of 85. Malignant Peripheral Nerve Sheath Tumor (MPNST), a common malignancy in patients with Neurofibromatosis, and colorectal cancer are midkine- producing tumors with high mortality rates. In vitro and preclinical xenograft models of MPNST were utilized in this dissertation to study the role of midkine (MDK), a tumor-specific gene over- expressed in these tumors and to test the efficacy of a MDK-transcriptionally targeted oncolytic HSV-1 (oHSV).
    [Show full text]
  • Genome Provides Insights Into Vertebrate Evolution
    ARTICLES OPEN Sequencing of the sea lamprey (Petromyzon marinus) genome provides insights into vertebrate evolution Jeramiah J Smith1,2, Shigehiro Kuraku3,4, Carson Holt5,37, Tatjana Sauka-Spengler6,37, Ning Jiang7, Michael S Campbell5, Mark D Yandell5, Tereza Manousaki4, Axel Meyer4, Ona E Bloom8,9, Jennifer R Morgan10, Joseph D Buxbaum11–14, Ravi Sachidanandam11, Carrie Sims15, Alexander S Garruss15, Malcolm Cook15, Robb Krumlauf15,16, Leanne M Wiedemann15,17, Stacia A Sower18, Wayne A Decatur18, Jeffrey A Hall18, Chris T Amemiya2,19, Nil R Saha2, Katherine M Buckley20,21, Jonathan P Rast20,21, Sabyasachi Das22,23, Masayuki Hirano22,23, Nathanael McCurley22,23, Peng Guo22,23, Nicolas Rohner24, Clifford J Tabin24, Paul Piccinelli25, Greg Elgar25, Magali Ruffier26, Bronwen L Aken26, Stephen M J Searle26, Matthieu Muffato27, Miguel Pignatelli27, Javier Herrero27, Matthew Jones6, C Titus Brown28,29, Yu-Wen Chung-Davidson30, Kaben G Nanlohy30, Scot V Libants30, Chu-Yin Yeh30, David W McCauley31, James A Langeland32, Zeev Pancer33, Bernd Fritzsch34, Pieter J de Jong35, Baoli Zhu35,37, Lucinda L Fulton36, Brenda Theising36, Paul Flicek27, Marianne E Bronner6, All rights reserved. Wesley C Warren36, Sandra W Clifton36,37, Richard K Wilson36 & Weiming Li30 Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ~500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and America, Inc. assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species.
    [Show full text]
  • Regulation of NF-Κb Signaling by the A20 Deubiquitinase
    Cellular & Molecular Immunology (2012) 9, 123–130 ß 2012 CSI and USTC. All rights reserved 1672-7681/12 $32.00 www.nature.com/cmi REVIEW Regulation of NF-kB signaling by the A20 deubiquitinase Noula Shembade and Edward W Harhaj The NF-kB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-kBis achieved by K63-linked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IkB kinase (IKK). Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-kB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas. Cellular & Molecular Immunology (2012) 9, 123–130; doi:10.1038/cmi.2011.59; published online 20 February 2012 Keywords: A20; inflammation; NF-kB; ubiquitin INTRODUCTION covalently attached to lysine residues on protein substrates and either The NF-kB transcription factor is ubiquitously expressed and is triggers proteasomal degradation, protein trafficking, signal transduc- activated by diverse immune stimulatory ligands, including inter- tion or the DNA damage response. Ubiquitination involves a three-step leukin-1b (IL-1b), tumor necrosis factor-a (TNF-a), bacterial lipo- enzymatic reaction catalyzed by three classes of proteins: E1 ubiquitin- polysaccharide (LPS) and antigenic peptides.
    [Show full text]