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Dendritic Cells Transcriptome and Regulate the Function Of Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells This information is current as Danielle A. de Verteuil, Alexandre Rouette, Marie-Pierre of September 25, 2021. Hardy, Stéphanie Lavallée, Assya Trofimov, Étienne Gaucher and Claude Perreault J Immunol published online 23 June 2014 http://www.jimmunol.org/content/early/2014/06/22/jimmun ol.1400871 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/06/22/jimmunol.140087 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 September 25, 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 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published June 23, 2014, doi:10.4049/jimmunol.1400871 The Journal of Immunology Immunoproteasomes Shape the Transcriptome and Regulate the Function of Dendritic Cells Danielle A. de Verteuil,*,†,1 Alexandre Rouette,*,†,1 Marie-Pierre Hardy,*,† Ste´phanie Lavalle´e,* Assya Trofimov,* E´ tienne Gaucher,* and Claude Perreault*,† By regulating protein degradation, constitutive proteasomes (CPs) control practically all cellular functions. In addition to CPs, vertebrates express immunoproteasomes (IPs). The major nonredundant role ascribed to IPs is their enhanced ability to generate antigenic peptides. We report that CPs and IPs differentially regulate the expression of >8000 transcripts in maturing mouse dendritic cells (DCs) via regulation of signaling pathways such as IFN regulatory factors, STATs, and NF-kB. IPs regulate the transcription of many mRNAs and maturation of a few of them. Moreover, even when engineered to present optimal amounts of antigenic peptide, IP-deficient DCs are inefficient for in vivo T cell priming. Our study shows that the role of IPs in DCs is not limited to Ag processing and reveals a major nonredundant role for IPs in transcription regulation. The dramatic effect of IPs on Downloaded from the transcriptional landscape could explain the various immune and nonimmune phenotypes observed in vertebrates with IP deficiency or mutations. The Journal of Immunology, 2014, 193: 000–000. n all eukaryotes, proteolysis of a variety of cellular proteins by or inhibition of IP subunits can affect several immune cell functions constitutive proteasomes (CPs) plays an important role in independently of MIP processing: T cell proliferation, B cell sur- I many basic cellular processes including regulation of cell vival, and cytokine production (10, 11). Moreover, the expression of http://www.jimmunol.org/ cycle and division, differentiation and development, morphogen- IPs in numerous nonimmune cells from noninflamed tissues sug- esis, and response to stress (1). Vertebrates also express immu- gests that the roles of IPs are not limited to the immune system. noproteasomes (IPs), in which the catalytic b-subunits are re- Thus, IPs have been implicated in adipocyte differentiation (12), placedbyIFN-g–inducible homologs: LMP2 (aka b1i, Psmb9) maintenance of pluripotency in embryonic stem cells (13), response for b1(Psmb6), MECL1 (aka b2i, Psmb10) for b2(Psmb7), and to injury in the retina and brain (14), and neoplastic transformation LMP7 (aka b5i, Psmb8)forb5(Psmb5). The best-described non- (15). However, the mechanisms responsible for the various pheno- redundant role ascribed to IPs is their enhanced ability to generate types observed in vertebrates with IP deficiency or mutations re- MHC class I–associated peptides (MIPs) (2–5). main elusive. As regulators of protein degradation, proteasomes regulate The proteolytic subunits of CPs are known to regulate gene ex- by guest on September 25, 2021 practically all cellular functions (1, 6, 7). It is therefore logical to pression, typically via cleavage of transcriptional regulators (16). assume that replacement of CPs by IPs could have pleiotropic and Because CPs and IPs display distinct substrate preferences (4, 17), far reaching effects on cell function (8, 9). In line with this, deletion we hypothesized that they might have nonredundant effects on gene expression. This assumption was supported by preliminary gene expression microarray experiments showing that several transcripts *Institute for Research in Immunology and Cancer, University of Montreal, Montreal, are differentially expressed in wild-type (WT) and IP-deficient Quebec H3C 3J7, Canada; and †Department of Medicine, University of Montreal, Montreal, Quebec H3C 3J7, Canada dendritic cells (DCs) (4). The goal of our work was therefore to 1D.A.d.V. and A.R. contributed equally to this work. evaluate the global impact of IPs on gene expression, discover its underlying mechanisms, and evaluate its in vivo relevance. Received for publication April 8, 2014. Accepted for publication May 23, 2014. Based on multidimensional profiling of WT and Lmp72/2Mecl12/2 This work was supported by grants from the Canadian Institutes for Health Research (CIHR) (MOP 42384) and the Canadian Cancer Society (Grant 701564). The Insti- (double knockout [dKO]) DCs, we report that IPs regulate the tute for Research in Immunology and Cancer is supported in part by the Canada expression of .8000 transcripts in maturing DCs. The broad impact Foundation for Innovation and the Fonds de Recherche Que´bec Sante´ (FRQS). of IPs on gene expression is cell autonomous, mediated mainly at D.A.d.V. and A.R. were supported by doctoral research awards from FRQS and CIHR, respectively. E.G. was supported by a studentship from the De´fiPerse´ve´rance-Famille the transcriptional level, and likely involves major signaling path- Gosselin Fund. C.P. holds a Canada Research Chair in Immunobiology. ways including IFN regulatory factors (IRFs), NF-kB, and STATs. RNA sequencing data presented in this article have been submitted to the Gene Furthermore, even when engineered to present similar levels of Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession number a model epitope, dKO DCs were less effective than WT DCs in GSE52616. priming T cells in vivo. We conclude that IPs have pervasive effects Address correspondence and reprint requests to Prof. Claude Perreault, Institute for Research in Immunology and Cancer, P.O. Box 6128, Station Centre-Ville, Montreal, on gene transcription and may thereby regulate fundamental cellular QC H3C 3J7, Canada. E-mail address: [email protected] processes in DCs. The online version of this article contains supplemental material. Abbreviations used in this article: cDC, conventional DC; CP, constitutive protea- Materials and Methods some; DC, dendritic cell; DEG, differentially expressed gene; dKO, double knockout; GO, gene ontology; H2A, histone 2A; H2B, histone 2B; IP, immunoproteasome; IPA, Mice and DC culture Ingenuity Pathway Analysis; IRF, IFN regulatory factor; IRIC, Institute for Research Mice on a C57BL/6 or B6.SJL background were housed at the Institute for in Immunology and Cancer; MIP, MHC class I–associated peptide; NP-40, Nonidet 2/2 P-40; ubH2A, ubiquitylated histone 2A; ubH2B, ubiquitylated histone 2B; WT, wild- Research in Immunology and Cancer (IRIC) animal facility. Lmp7 2/2 2/2 type. Mecl1 (dKO) and Mecl1 mice were generously provided by Dr. T.A. Griffin from the Medicine College of the University of Cincinnati 2 2 Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 and Lmp7 / mice by Dr. H.J. Fehling from the Institute of immunology, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400871 2 IMMUNOPROTEASOMES REGULATE TRANSCRIPTION University Clinics Ulm. OT-1 on a Rag22/2 background mice were pur- and upstream regulator analysis was performed from which we extracted chased from Taconic Farms. All protocols using animals conformed to the most drastically affected molecules described as “transcriptional reg- the local law and regulations and have been approved by Universite´ de ulators” (p , 0.05 with right-tailed Fisher exact test). The IPA’s z-score Montre´al’s Comite´ de de´ontologie de l’expe´rimentation sur les animaux. algorithm was used to predict the direction of change for a given regulator Bone marrow–derived DCs were generated from 8–12-wk-old mice, and (increase [z-score $ 2] or decrease [z-score #22]) depending on the maturation was induced with LPS (Sigma-Aldrich), as described (4). For dKO/WT ratio of expression of its target genes within a cluster, for each coculture experiment of B6.SJL WT and C57BL/6 bone marrow–derived time point (no LPS and 1-, 2-, and 6-h LPS). For each cluster, a map DCs, sorting was performed on DCs stimulated overnight with LPS. was generated with any given regulator that had a p value #0.05 and a Harvested cells were treated for 20 min with Fc Block CD16/CD32 (BD z-score $2or#22 at one of the time points. Regulators passing these Biosciences) before staining with anti-CD11c (PECy7; BD Biosciences), two thresholds were highlighted.
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