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Preference and Lysosomal Localization Acid Oxidase with An IL-4-Induced Gene-1 Is a Leukocyte l-Amino Acid Oxidase with an Unusual Acidic pH Preference and Lysosomal Localization This information is current as James M. Mason, Mamta D. Naidu, Michele Barcia, Debra of September 28, 2021. Porti, Sangeeta S. Chavan and Charles C. Chu J Immunol 2004; 173:4561-4567; ; doi: 10.4049/jimmunol.173.7.4561 http://www.jimmunol.org/content/173/7/4561 Downloaded from References This article cites 47 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/173/7/4561.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 28, 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 © 2004 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology IL-4-Induced Gene-1 Is a Leukocyte L-Amino Acid Oxidase with an Unusual Acidic pH Preference and Lysosomal Localization1 James M. Mason,* Mamta D. Naidu,† Michele Barcia,* Debra Porti,* Sangeeta S. Chavan,† and Charles C. Chu2† IL-4-induced gene-1 (Il4i1 or Fig1) initially isolated as a gene of unknown function from mouse B lymphocytes, is limited in expression to primarily immune tissues and genetically maps to a region of susceptibility to autoimmune disease. The predicted Il4i1 protein (IL4I1) sequence is most similar to apoptosis-inducing protein and Apoxin I, both L-amino acid oxidases (LAAO; Enzyme Commission 1.4.3.2). We demonstrate that IL4I1 has unique LAAO properties. IL4I1 has preference for aromatic amino acid substrates, having highest specific activity with phenylalanine. In support of this selectivity, IL4I1 is inhibited by aromatic competitors (benzoic acid and para-aminobenzoic acid), but not by nonaromatic LAAO inhibitors. Il4i1 protein and enzyme activity is found in the insoluble fraction of transient transfections, implying an association with cell membrane and possibly Downloaded from intracellular organelles. Indeed, IL4I1 has the unique property of being most active at acidic pH (pH 4), suggesting it may reside preferentially in lysosomes. IL4I1 is N-linked glycosylated, a requirement for lysosomal localization. Confocal microscopy of cells expressing IL4I1 translationally fused to red fluorescent protein demonstrated that IL4I1 colocalized with GFP targeted to lysosomes and with acriflavine, a green fluorescent dye that is taken up into lysosomes. Thus, IL4I1 is a unique mammalian LAAO targeted to lysosomes, an important subcellular compartment involved in Ag processing. The Journal of Immunology, 2004, 173: 4561–4567. http://www.jimmunol.org/ nterleukin-4-induced gene-1 (Il4i13 or Fig1) was initially iso- cated by a locus or loci derived from the NZW mouse strain (8– lated in a screen for IL-4-induced genes from mouse B cells 10). Interestingly, the NZW allele for Il4i1 contains three amino I using cDNA representational difference analysis (1, 2). Re- acid substitutions (11), which could alter a function that results in cently, Fig1 was renamed Il4i1 in keeping with recommendations SLE susceptibility. Furthermore, the Sle3 susceptibility locus from from the Human Gene Nomenclature Committee (3). Il4i1 may this region appears to be expressed primarily in APCs (12), where play an important role in the immune system for several reasons. we have also detected Il4i1 expression. Finally, the human Il4i1 It is induced in an immediate-early fashion by IL-4, a key regulator ortholog is located on chromosome 19q13.3–19q13.4 (11) in a of the immune response (4); its expression is strikingly limited to region that is a hot spot for autoimmune disease susceptibility in by guest on September 28, 2021 immune tissues, with clear expression in B cells (1, 5); and it is general, including rheumatoid arthritis, multiple sclerosis, insulin- also found in professional APCs (dendritic cells (DC) and macro- dependent diabetes mellitus, and SLE (13–15). Thus, an alteration phages) (6, 48). in Il4i1 could contribute to autoimmune disease in both mouse Mouse Il4i1 genetically maps to chromosome 7 between the and man. Klk6 and Fut1 genes (23.1 cM; Mouse Genome Database, Mouse One clue to the function of Il4i1 is its sequence similarity to Genome Informatics; The Jackson Laboratory, Bar Harbor, ME; L-amino acid oxidases (LAAO; Enzyme Commission (EC) www.informatics.jax.org (July 2004)) (1, 7), a region where sus- 1.4.3.2) (Fig. 1). The cDNA sequences of both mouse and hu- ceptibility to systemic lupus erythematosus (SLE) has been impli- man Il4i1 predict a protein containing a putative signal peptide sequence for entry into the endoplasmic reticulum (ER), a re- *Gene Therapy Vector Laboratory, and †Laboratory of Gene Activation, North Shore- gion of similarity to LAAO, and a C-terminal region with no Long Island Jewish Research Institute, and Departments of Medicine, North Shore University Hospital and New York University School of Medicine, Manhasset, NY homology to known proteins (1, 11). The LAAO region of sim- 11030 ilarity most closely resembles apoptosis-inducing protein found Received for publication June 18, 2003. Accepted for publication July 23, 2004. in fish (43% identical over 485 aa) (16) and snake venom The costs of publication of this article were defrayed in part by the payment of page LAAO (37% identical over 484 aa) (17), also known as Apoxin charges. This article must therefore be hereby marked advertisement in accordance I (18). The LAAO-similar portion conserves key domains and with 18 U.S.C. Section 1734 solely to indicate this fact. residues that bind the flavin adenine dinucleotide (FAD) cofac- 1 This work was supported in part by the North Shore-Long Island Jewish Research Institute, the Muriel Fusfeld Foundation, the Leonard Wagner Autoimmunity Fund, tor required for its enzymatic activity, as well as residues in the the SLE Foundation, and U.S. Public Health Service Grant AI44837 awarded by the active site of the LAAO crystal structure (11, 19). National Institutes of Health. Because of the similarity of IL4I1 to LAAO, we examined the 2 Address correspondence and reprint requests to Dr. Charles C. Chu, Laboratory of LAAO enzyme reaction catalyzed by IL4I1. LAAO catalyzes the Gene Activation, North Shore-Long Island Jewish Research Institute, and Depart- ments of Medicine, North Shore University Hospital and New York University oxidation of L-amino acid to 2-oxo acid, via an L-imino acid in- School of Medicine, 350 Community Drive, Manhasset, NY 11030. E-mail address: termediate (20) (Fig. 2). Water and oxygen are required in this [email protected] reaction resulting in hydrogen peroxide (H O ) and ammonia by- 3 Abbreviations used in this paper: Il4i1, IL-4-induced gene-1; IL4I1, Il4i1 protein; 2 2 DC, dendritic cell; SLE, systemic lupus erythematosus; LAAO, L-amino acid oxidase; products. We developed an enzyme assay demonstrating that IL4I1 ER, endoplasmic reticulum; FAD, flavin adenine dinucleotide; EGFP, enhanced GFP is the first LAAO found in immune cells. Although IL4I1 has gene; IRES, internal ribosome entry site; dsRED, Discosom red fluorescent protein; BA, benzoic acid; PABA, para-aminobenzoic acid; diacetyl, 2,3-butanedione; 2H3B, similar enzyme kinetics to other LAAO from other cells and or- 2-hydroxy-3-butynoic acid. ganisms, it is most reactive with aromatic amino acids at acidic Copyright © 2004 by The American Association of Immunologists, Inc. 0022-1767/04/$02.00 4562 IL4I1 IS A LEUKOCYTE LAAO WITH LYSOSOMAL LOCALIZATION FIGURE 1. IL4I1 is most similar to LAAO. Schematic of mouse IL4I1 is shown to scale with N-linked glycosylation sites (N-Gly) (f) and po- tential tyrosine (Y) phosphorylation sites (E). Predicted FAD cofactor binding domains are indicated by white boxes in the schematic correspond- ing to the three black lines underneath. The signal peptide and short regions of similarity to many known FAD-binding proteins (MANY) and to spe- FIGURE 2. LAAO reaction. The chemical structure of L-phenylalanine cific proteins (phytoene desaturase (PDS), monoamine oxidase (MAO), is shown as a typical L-amino acid oxidized by LAAO. LAAO is indicated and tryptophan 2-monooxygenase (TMO)) are shown by the next row of with the FAD cofactor and its oxidation state. The reaction is shown in two black lines underneath the schematic, corresponding to the gray-spotted steps, with an L-imino acid intermediate. boxes. Regions of similarity to bacterial (Bacillus cereus) and eukaryotic Downloaded from (fish (Scomber japonicus) and snake (Crotalus atrox, C. adamanteus)) LAAO are shown by the remaining black lines underneath the schematic of solution, extracted with phenol/chloroform mixture, and then precipitated IL4I1. with isopropanol. The resulting RNA was resuspended in 20–50 ␮lof diethyl-pyrocarbonate-treated H2O and quantitated using UV absorption pH. Because acidic pH preference is a common feature of lysoso- measurements at 260/280 nm. For first-strand cDNA synthesis of RT-PCR, 7 ␮l of RNA (200–1000 mal enzymes, we investigated the subcellular localization of IL4I1 ng) plus 2 ␮lof10␮M oligo(dT) (5Ј-TTT TTT TTT TTT TTT V) was http://www.jimmunol.org/ and found that it is the first known LAAO that is targeted to ly- heated at 65°C for 5 min, cooled at room temperature, and then kept on ice.
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