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Osa-Containing Brahma Complex Regulates Innate Immunity and the Expression of Metabolic Genes in Drosophila

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Osa-Containing Brahma Complex Regulates Innate Immunity and the Expression of Metabolic Genes in Drosophila This information is current as Susanna Valanne, Mirva Järvelä-Stölting, Sanna-Kaisa E. of October 1, 2021. Harjula, Henna Myllymäki, Tiina S. Salminen and Mika Rämet J Immunol published online 20 March 2020 http://www.jimmunol.org/content/early/2020/03/19/jimmun ol.1900571 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2020/03/19/jimmunol.190057 Material 1.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 1, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts Errata An erratum has been published regarding this article. Please see next page or: /content/206/4/917.full.pdf The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2020 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 20, 2020, doi:10.4049/jimmunol.1900571 The Journal of Immunology Osa-Containing Brahma Complex Regulates Innate Immunity and the Expression of Metabolic Genes in Drosophila Susanna Valanne,*,1 Mirva Ja¨rvela¨-Sto¨lting,*,1 Sanna-Kaisa E. Harjula,* Henna Myllyma¨ki,*,2 Tiina S. Salminen,*,† and Mika Ra¨met*,‡,x,{ Negative regulation of innate immunity is essential to avoid autoinflammation. In Drosophila melanogaster, NF-kB signaling– mediated immune responses are negatively regulated at multiple levels. Using a Drosophila RNA interference in vitro screen, we identified a set of genes inhibiting immune activation. Four of these genes encode members of the chromatin remodeling Osa- containing Brahma (BAP) complex. Silencing additional two genes of the BAP complex was shown to have the same phenotype, confirming its role in immune regulation in vitro. In vivo, the knockdown of osa and brahma was shown to enhance the expression of the Toll pathway–mediated antimicrobial peptides when the flies were challenged with Gram-positive bacteria Micrococcus Downloaded from luteus. In this setting, osa knockdown had a particularly strong effect on immune effectors that are predominantly activated by the Imd pathway. Accordingly, Drosophila NF-kB Relish expression was increased by osa silencing. These transcriptional changes were associated with enhanced survival from M. luteus + E. faecalis infection. Besides regulating the expression of immune effector genes, osa RNA interference decreased the expression of a large group of genes involved in metabolism, particularly proteolysis. Of note, the expression of the recently characterized, immune-inducible gene Induced by Infection (IBIN) was diminished in osa knockdown flies. Although IBIN has been shown to modulate metabolism upon infection, the expression of selected Osa-regulated http://www.jimmunol.org/ metabolism genes was not rescued by overexpressing IBIN. We conclude that the BAP complex regulates expression of genes involved in metabolism at least partially independent or downstream of IBIN. Moreover, Osa affects the NF-kB–mediated immune response by regulating Drosophila NF-kB factor Relish expression. The Journal of Immunology, 2020, 204: 000–000. he fruit fly Drosophila melanogaster is an established pathways, the Toll and the Immune deficiency (Imd) pathway (6–8). model to study mechanisms of innate immunity (1), in- The Imd pathway is activated when bacteria containing a DAP-type cluding both cellular and humoral responses (2, 3). Mo- peptidoglycan in their cell wall (9, 10) are recognized by the T by guest on October 1, 2021 lecular mechanisms of infection have been extensively studied by pathway receptor PGRP-LC (11–13). The activated signal is using the Drosophila model, and the evolutionary conservation of transduced forward to activate a dimer of NF-kB transcription immune signaling proteins from fruit fly to human has been factors. The Toll pathway is activated by bacteria with a Lys-type demonstrated. Many sophisticated mechanisms are involved in the peptidoglycan in their cell wall (many Gram-positive bacteria) or activation of the cellular immune response when non-self material the fungal b-1,3-glucan (14–16). Activation elicits proteolytic are present, including recognition, phagocytosis, and encapsulation cascades of activator proteins and ultimately the cleavage of and the killing of parasites (4, 5). The humoral immune response Spa¨tzle (Spz) to produce an activated ligand of the pathway (17, leads to the production of antimicrobial peptides and is mainly 18). Activation of the Toll pathway also leads to the activation mediated by two evolutionarily conserved NF-kB signaling and dimerization of NF-kB transcription factors (reviewed in *Laboratory of Experimental Immunology, Faculty of Medicine and Health Technol- performed the in vivo experiments; all authors analyzed their own data, S.V., M.J.-S., ogy, 33014 Tampere University, Tampere, Finland; †Laboratory of Mito-Immuno- T.S.S., and M.R. wrote the paper; and all authors read and approved the manuscript. Metabolism, Faculty of Medicine and Health Technology, 33014 Tampere University, The dataset presented in this article has been submitted to the Gene Expression Tampere, Finland; ‡PEDEGO Research Unit, Faculty of Medicine, 90014 University x omnibus under accession number GSE120443 (https://www.ncbi.nlm.nih.gov/geo/ of Oulu, Oulu, Finland; Medical Research Center Oulu, 90014 University of Oulu, { query/acc.cgi?acc=GSE120443). Oulu, Finland; and Department of Children and Adolescents, Oulu University Hos- pital, 90014 University of Oulu, Oulu, Finland Address correspondence and reprint requests to Prof. Mika Ra¨met, Laboratory of Experimental Immunology, Faculty of Medicine and Health Technology, Arvo 1S.V. and M.J.-S. contributed equally. Ylpo¨nKatu34,33014TampereUniversity,Tampere, Finland. E-mail address: 2Current address: University of Edinburgh Centre for Inflammation Research, mika.ramet@tuni.fi Queen’s Medical Research Institute, Edinburgh BioQuarter, Edinburgh, U.K. The online version of this article contains supplemental material. ORCIDs: 0000-0003-0898-8423 (S.V.); 0000-0002-5380-6628 (M.J.-S.); 0000-0003- Abbreviations used in this article: Bap60, Brahma associated protein 60 kD; 3750-2779 (S.-K.E.H.); 0000-0002-7232-0754 (T.S.S.). Bap111, Brahma associated protein 111 kD; BomS1, Bomanin Short 1; BomS2, Received for publication May 21, 2019. Accepted for publication February 12, 2020. Bomanin Short 2; brm, brahma; CecA1, Cecropin A1; dom, domino; DptB, Dipter- icin B; Drs-luc, Drosomycin-luciferase; FC, fold change; FDR, false discovery This work was supported by the Sigrid Juselius Foundation, the Academy of Finland rate; GO, Gene Ontology; IkB, inhibitor of kB; IBIN, Induced by Infection;Imd, (Grant 277495), the Competitive State Research Financing of the Expert Responsi- Immune deficiency; IntS5, Integrator 5; IntS6, Integrator 6; IntS8, Integrator 8; bility Area of Oulu University Hospital and the Tampere Tuberculosis Foundation (to mor, moira; p.i., postinfection; PB, polybromo; PCA, principal component analy- M.R.), the Academy of Finland (Grants 322732 and 328979) (to T.S.S.), and the sis; qRT-PCR, quantitative real-time PCR; RNAi, RNA interference; SNF, sucrose Maud Kuistila Memorial Foundation (to H.M.). The Tampere Drosophila Core Fa- nonfermenting; Snr1, Snf5-related 1; SP, serine protease; Spz, Spa¨tzle;SWI, cility, providing resources for fly work, is partially funded by Biocenter Finland. switching defective; VDRC, Vienna Drosophila Resource Center. S.V., M.J.-S., T.S.S., and M.R. designed the experiments; S.-K.E.H. and H.M. per- formed the in vitro RNA interference screen experiments; S.V., M.J.-S., and T.S.S. Copyright Ó 2020 by The American Association of Immunologists, Inc. 0022-1767/20/$37.50 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900571 2 THE BAP COMPLEX IN DROSOPHILA IMMUNITY AND METABOLISM Ref. 6). Relish is the NF-kB factor for the Imd pathway (19), negative control, GFP was carried out using the pMT/BiP/V5-His/GFP whereas Dorsal and Dif are NF-kB factors activated via the Toll plasmid (Invitrogen) as template. dsRNAs were produced from the nes- pathway (20, 21). Although NF-kB factors are normally thought ted PCR templates by in vitro transcription using the T7 MegaScript RNA polymerase (Ambion) according to the manufacturer’s instructions. to function as homodimers, it has been shown that heterodimers between different NF-kB factors do form (22, 23). This changes Luciferase reporter assay and dsRNA treatments the pattern of antimicrobial peptide expression regulated by Luciferase reporter assays were performed essentially as described earlier the NF-kB factors and produces a broader spectrum of host (37). Briefly, for activating the Toll pathway by transfection, S2 cells responses. were transfected either with 0.2 mgoftheToll10b plasmid, encoding a m Activation of immune responses requires strict control to avoid constitutively active form of the Toll receptor (39) or
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    Getting “Under the Skin”: Human Social Genomics in the Multi-Ethnic Study of Atherosclerosis by Kristen Monét Brown A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Epidemiological Science) in the University of Michigan 2017 Doctoral Committee: Professor Ana V. Diez-Roux, Co-Chair, Drexel University Professor Sharon R. Kardia, Co-Chair Professor Bhramar Mukherjee Assistant Professor Belinda Needham Assistant Professor Jennifer A. Smith © Kristen Monét Brown, 2017 [email protected] ORCID iD: 0000-0002-9955-0568 Dedication I dedicate this dissertation to my grandmother, Gertrude Delores Hampton. Nanny, no one wanted to see me become “Dr. Brown” more than you. I know that you are standing over the bannister of heaven smiling and beaming with pride. I love you more than my words could ever fully express. ii Acknowledgements First, I give honor to God, who is the head of my life. Truly, without Him, none of this would be possible. Countless times throughout this doctoral journey I have relied my favorite scripture, “And we know that all things work together for good, to them that love God, to them who are called according to His purpose (Romans 8:28).” Secondly, I acknowledge my parents, James and Marilyn Brown. From an early age, you two instilled in me the value of education and have been my biggest cheerleaders throughout my entire life. I thank you for your unconditional love, encouragement, sacrifices, and support. I would not be here today without you. I truly thank God that out of the all of the people in the world that He could have chosen to be my parents, that He chose the two of you.