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PRDM1/BLIMP-1 Modulates IFN-γ -Dependent Control of the MHC Class I Antigen-Processing and Peptide-Loading Pathway This information is current as of September 26, 2021. Gina M. Doody, Sophie Stephenson, Charles McManamy and Reuben M. Tooze J Immunol 2007; 179:7614-7623; ; doi: 10.4049/jimmunol.179.11.7614 http://www.jimmunol.org/content/179/11/7614 Downloaded from References This article cites 67 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/179/11/7614.full#ref-list-1 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 26, 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 © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology PRDM1/BLIMP-1 Modulates IFN-␥-Dependent Control of the MHC Class I Antigen-Processing and Peptide-Loading Pathway1 Gina M. Doody,* Sophie Stephenson,* Charles McManamy,† and Reuben M. Tooze2* A diverse spectrum of unique peptide-MHC class I complexes guides CD8 T cell responses toward viral or stress-induced Ags. Multiple components are required to process Ag and facilitate peptide loading in the endoplasmic reticulum. IFN-␥, a potent proinflammatory cytokine, markedly up-regulates transcription of genes involved in MHC class I assembly. Physiological mech- anisms which counteract this response are poorly defined. We demonstrate that promoters of functionally linked genes on this pathway contain conserved regulatory elements that allow antagonistic regulation by IFN-␥ and the transcription factor B lymphocyte-induced maturation protein-1 (also known as PR domain-containing 1, with ZNF domain (PRDM1)). Repression of ERAP1, TAPASIN, MECL1, and LMP7 by PRDM1 results in failure to up-regulate surface MHC class I in response to IFN-␥ in Downloaded from human cell lines. Using the sea urchin prdm1 ortholog, we demonstrate that the capacity of PRDM1 to repress the IFN response of such promoters is evolutionarily ancient and that dependence on the precise IFN regulatory factor element sequence is highly conserved. This indicates that the functional interaction between PRDM1 and IFN-regulated pathways antedates the evolution of the adaptive immune system and the MHC, and identifies a unique role for PRDM1 as a key regulator of Ag presentation by MHC class I. The Journal of Immunology, 2007, 179: 7614–7623. http://www.jimmunol.org/ he MHC class I system is first evident early in the evo- (MECL1), to generate the immunoproteasome (3). It acts to facil- lution of jawed vertebrates at the inception of the “adap- itate the transport of such peptides into the endoplasmic reticulum T tive” or “anticipatory” type immune response (1). The (ER), where the MHC class I peptide complex is assembled, by MHC class I Ag-processing and -presentation pathways co-opted inducing the expression of the peptide transporters TAP1 and and adapted existing cellular machinery to allow the sampling of TAP2 (4, 5). It enhances the expression of the TAP-associated proteins during normal and altered cellular conditions and subse- chaperone protein TAPASIN which facilitates peptide loading into quent presentation to CD8-restricted T cells (2). The immune sys- the MHC class I-binding groove (6, 7) and ER amino peptidase 1 tem has evolved the ability to change the pattern of peptide pre- (ERAP1) (8, 9), which is responsible for trimming peptides to fit by guest on September 26, 2021 sentation in response to inflammatory cues by adapting the cellular the groove, a function vital to the generation of the mature peptide machinery engaged in the generation of the peptide repertoire. For repertoire (10). example, in the context of viral infection or inflammation, IFN-␥ The cumulative effects of IFN-␥ therefore provide the cell with modulates not only the transcription of the MHC class I genes, but both qualitatively different peptides and a quantitative increase in also multiple components of the Ag-processing and -loading path- surface MHC expression with which to elicit T cell activation. ways. IFN-␥ enhances the generation of peptides of an appropriate Changes in the peptide repertoire can lead to inappropriate de- length for presentation by inducing the expression of alternate pro- structive immune responses and contribute to the initiation of au- 3 teasome components, large multifunctional peptidase 2 (LMP2) , toimmune disease (11). The response to IFN-␥ provides a para- LMP7, and multicatalytic endopeptidase complex subunit-1 digm for the transcriptional control of MHC class I-dependent Ag presentation (3). Although the mechanisms for activation have *Section of Experimental Haematology, Leeds Institute of Molecular Medicine, and been extensively studied, the endogenous factors mediating oppos- †Academic Unit of Oncology and Haematology, Haematological Malignancy Diag- ing or repressive effects on IFN-␥-induced transcription to main- nostic Service, University of Leeds, Leeds, United Kingdom tain normal levels of MHC class I expression and unaltered peptide Received for publication February 16, 2007. Accepted for publication September 11, 2007. repertoires are ill-defined. Nevertheless, the tight control inherent in other aspects of the immune response suggests that these are The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance likely to exist. with 18 U.S.C. Section 1734 solely to indicate this fact. B lymphocyte-induced maturation protein-1 (BLIMP-1), 1 This work was supported by a Medical Research Council Clinician Scientist Fel- which is also known as PR domain-containing 1, with ZNF lowship (to R.M.T). domain (PRDM1), is an evolutionarily conserved transcrip- 2 Address correspondence and reprint requests to Dr. Reuben M. Tooze, Section of tional repressor of the Kru¨ppel family of zinc finger proteins Experimental Haematology, Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, (12–15), which acts both through direct competition for pro- U.K. E-mail address: [email protected] moter occupancy, and by recruiting epigenetic modifiers (16– 3 Abbreviations used in this paper: LMP, large multifunctional peptidase; MECL-1, 20). It is best known as a regulator of terminal B cell differen- multicatalytic endopeptidase complex subunit-1; ER, endoplasmic reticulum; ERAP1, ER amino peptidase-1; BLIMP-1, B lymphocyte-induced maturation protein-1; tiation (21, 22), but additional roles for PRDM1 have also been PRDM1, PR domain-containing 1, with ZNF domain; IRF, IFN regulatory factor; identified in the control of T cell (23, 24), macrophage (25), and IRF-E, IRF element; ChIP, chromatin immunoprecipitation; EGFP, enhanced GFP; sebaceous gland differentiation (26). The original identification siRNA, short interfering RNA. of PRDM1 as a postinduction repressor of the IFN␤ promoter Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 during cellular viral infection suggested that PRDM1 is a key www.jimmunol.org The Journal of Immunology 7615 regulator of cellular responses to IFNs (12). The optimum plasmid preparations. The data are from a representative experiment dis- PRDM1 DNA-binding sequence overlaps with the IFN regula- played as fold increase in light units relative to unstimulated cells cotrans- tory factor-element (IRF-E) (27, 28), and we recently showed fected with the empty vector. that PRDM1 has the ability to regulate an IFN-␥-responsive Antibodies promoter by competing with IRFs for occupancy of an IRF-E Rabbit antisera to PRDM1 have been described previously (19, 32). (19). Given these characteristics, PRDM1 is a candidate to act Rabbit polyclonal Abs to IRF-1 and IRF-2 were obtained from Santa as a transcriptional repressor controlling MHC class I-depen- Cruz Biotechnology. Nonimmune rabbit IgG was obtained from Upstate dent Ag-presentation pathways. Biotechnology. Abs used for flow cytometry were mouse IgG2a con- Only a subset of IRF-E sequences, among all IFN-␥-responsive jugated to PE (BD Biosciences) and monoclonal anti-human HLA-ABC gene regulatory elements, are potential targets for PRDM1-depen- conjugated to PE (clone W6/32; DakoCytomation). Mouse mAb to TA- PASIN, clone 16, was obtained from BD Biosciences, goat polyclonal dent repression (19, 28). In this study, we demonstrate that the Ab to human keratin (GTX28572) was obtained from GeneTex, and promoters of multiple linked genes on the MHC class I Ag-pro- mouse mAb to ␤-actin, clone AC15, was obtained from Sigma-Aldrich. cessing and -loading pathway contain conserved IRF-E sequences Secondary Abs for immunofluorescence were Alexa Fluor 488 donkey which allow competitive binding by PRDM1 and IRFs. PRDM1 anti-mouse, Alexa Fluor 594 donkey anti-rabbit, and biotinylated
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  • Advancing the Role of Gamma-Tocotrienol As Proteasomes Inhibitor: a Quantitative Proteomic Analysis of MDA-MB-231 Human Breast Cancer Cells

    Advancing the Role of Gamma-Tocotrienol As Proteasomes Inhibitor: a Quantitative Proteomic Analysis of MDA-MB-231 Human Breast Cancer Cells

    biomolecules Article Advancing the Role of Gamma-Tocotrienol as Proteasomes Inhibitor: A Quantitative Proteomic Analysis of MDA-MB-231 Human Breast Cancer Cells Premdass Ramdas 1,2, Ammu Kutty Radhakrishnan 3 , Asmahani Azira Abdu Sani 4 , Mangala Kumari 5, Jeya Seela Anandha Rao 6 and Puteri Shafinaz Abdul-Rahman 1,7,* 1 Department of Molecular Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia; [email protected] 2 Department of Medical Biotechnology, School of Health Sciences, International Medical University, 57000 Kuala Lumpur, Malaysia 3 Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway, 47500 Selangor, Malaysia; [email protected] 4 Malaysian Genome Institute, National Institute of Biotechnology, 43000 Bangi, Malaysia; [email protected] 5 Division of Human Biology, International Medical University, 57000 Kuala Lumpur, Malaysia; [email protected] 6 Division of Pathology, International Medical University, 57000 Kuala Lumpur, Malaysia; [email protected] 7 University of Malaya Centre of Proteomics Research (UMCPR), University of Malaya, 50603 Kuala Lumpur, Malaysia * Correspondence: [email protected] Received: 27 November 2019; Accepted: 14 December 2019; Published: 21 December 2019 Abstract: Tocotrienol, an analogue of vitamin E has been known for its numerous health benefits and anti-cancer effects. Of the four isoforms of tocotrienols, gamma-tocotrienol (γT3) has been frequently reported for their superior anti-tumorigenic activity in both in vitro and in vivo studies, when compared to its counterparts. In this study, the effect of γT3 treatment in the cytoplasmic and nuclear fraction of MDA-MB-231 human breast cancer cells were assessed using the label-free quantitative proteomics analysis.