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The Journal of Immunology, 2003, 170: 5354-5358.
Copyright © 2003 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Monarch-1: A Pyrin/Nucleotide-Binding Domain/Leucine-Rich Repeat Protein That Controls Classical and Nonclassical MHC Class I Genes1

Kristi L. Williams*, Debra J. Taxman*, Michael W. Linhoff*, William Reed{dagger} and Jenny P.-Y. Ting2,*

* Department of Microbiology-Immunology, Lineberger Comprehensive Cancer Center, and {dagger} Department of Pediatrics and Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, NC 27599


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Proteins containing a limited number of N-terminal motifs followed by nucleotide-binding domain and leucine-rich repeat regions are emerging as important regulators for immunity. A search of human genome scaffold databases has identified a large family of known and unknown genes, which we have recently called the CATERPILLER (caspase recruitment domain, transcription enhancer, r(purine)-binding, pyrin, lots of leucine repeats) gene family. This work describes the characterization of a new member, Monarch-1. Monarch-1 has four different splice forms due to the differential splicing of leucine-rich repeat motifs. It is expressed in cells of myeloid-monocytic origin. Affymetrix microarrays and small interfering RNA were used to elucidate the downstream effects of Monarch-1 expression in cells including those of myeloid-monocytic origin. These analyses show that Monarch-1 enhances nonclassical and classical MHC class I expression at the level of the promoter, RNA, and protein expression.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
A recently discovered family of genes containing a nucleotide-binding domain (NBD)3 and a leucine-rich repeat (LRR) linked to a limited number of distinct N-terminal domains is critical for apoptosis and immune and inflammatory disorders. In humans, we described at least 22 known and novel family members by searching genomic databases and called these the CATERPILLER (caspase recruitment domain, transcription enhancer, r(purine)-binding, pyrin, lots of leucine repeats) gene family (1). Some of these genes were previously called NBD-LRR/NACHT/PYPAF genes (2, 3, 4). Among the known mammalian NBD/LRR proteins, three are genetically linked to immunologic disorders. MHC2TA codes for class II transactivator (CIITA), the master regulator of MHC class II (MHC-II); genetic lesions in it result in bare lymphocyte syndrome (5). Nucleotide oligomerization domain/caspase-associated recruitment domain 15 (NOD2/CARD15) is linked to Crohn’s disease and Blau syndrome (6, 7, 8, 9). Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene, which encodes cryopyrin/PYPAF1, predispose patients to autoinflammatory disorders (10, 11). It is noteworthy that CIITA, nucleotide oligomerization domain (NOD2), and cold-induced autoinflammatory syndrome 1 (CIAS1) also share a restricted expression pattern in cells of the immune system (4, 12).

This study shows the identification and cloning of another CATERPILLER family member which we call Monarch-1. It is expressed by the monocytic-myeloid lineage, and controls classical and nonclassical MHC class I (MHC-I) genes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Reagents

[(Z)-1-[2-(2-aminoehtyl)-N-(2-ammonioethyl)amino]diazen-1-um-1,2-diolate] (DETA-NO), an inducer of nitric oxide, was used at 125 µmol/L (Alexis Biochemicals, San Diego, CA). IFN-{gamma} was used at 1000 U/ml, TGF-{beta} at 1 ng/ml, TNF-{alpha} at 20 ng/ml (Peprotech, Rocky Hill, NJ), and PMA (Sigma-Aldrich, St. Louis, MO) at 10 ng/ml.

Monarch-1 RT-PCR

To clone the N-terminal region the following primers were used: Monarch-1 N-term forward (F) 5'-GGGGTACCGCTACGAACCGCAGGCAGGGACG; Monarch-1 N-term reverse (R) 5'-CAGCCTGGTCACGTCCTGGTCTG-3'. To clone the suspected C-terminal region and identify LRR splice forms, the following primers were used: Monarch-1 C-term F 5'-CAGAAGGACATCAACTGTGAGAG; Monarch-1 C-term R 5'-GCTCTAGACAGCAGATAGGACCATTCAGCAG-3'. The One-Step RT-PCR kit (Qiagen, Valencia, CA) was used following the manufacturer’s protocol. For expression analysis, the primers were Monarch-1 pyr-NBD F 5'-TTGAGCGGATAAACAGGAAGGAC-3' and Monarch-1 pyr-NBD R 5'-ATCTCCCTGCAGTTGATGTAGAAG-3'.

5' RACE

5' RACE was performed using two gene-specific primers following the manufacturer’s protocol (Roche, Indianapolis, IN). The gene-specific primers were: SP-1-5'-CGTCTGGCTCAAAGAGGGTCTCTATC-3'; SP-2-5'-CTGCGGACATAGTCCCTGTAGGTTTC-3'. The longest clone was chosen as the 5' start of the Monarch-1 mRNA.

Cell lines

HeLa cells were transfected with 1 µg of pcDNA3-hemagglutinin (HA) vector or HA-tagged Monarch-1 via FUGENE (Roche) and selected with 500 µg/ml G418. U937 small interference RNA (siRNA) clones were selected with 500 µg/ml puromycin.

Cell preparation and purification

PBMC were isolated from buffy coats (American Red Cross, Durham, NC) using lymphocyte separation medium (ICN Pharmaceuticals, Costa Mesa, CA). T cells, B cells, monocytes, and CD15+ granulocytes were individually selected by a MACS column (Miltenyi Biotec, Auburn, CA). Monocyte-derived dendritic cells were generated by differentiating PBMCs with GM-CSF and IL-4 for 8 days.

RNA preparation and real-time PCR

Total RNA was isolated using the SV40 Total RNA System (Promega, Madison, WI) with a DNase I digestion step. Real-time PCR was performed with the TaqMan sequence detection system (Applied Biosystems, Foster City, CA). Monarch-1 F 5'-AGAGGACCTGGTGAGGGATAC-3', R 5'-CTTCCAGAAGGCATGTTGAC-3', probe 5'- CCCGTCCTCACTTGGGAACCA-3'; HLA-G F 5'-AGACCCTGCCGCGCTACT-3', R 5'-TCCACTGGAGGGTGTGAGAAC-3', probe 5'-AACCAGAGCGAGGCC-3'; HLA-B F 5'-GGGACCGGGAGACACAGAT-3', R 5'-GCGCAGGTTCTCTCGGTAAG-3', probe 5'-CAAGACCAACACACAG-3'; LMP7b F 5'-GCCGCAGGGCTATTGCTTA-3', R 5'-CATATTGACAACGCCTCCAGAA-3', probe 5'-CACTCACAGAGACAGCT-3'; GAPDH F 5'-ACCTCAACTACATGGTTTAC-3', R 5'-GAAGATGGTGATGGGATTTC-3', probe 5'-CAAGCTTCCCGTTCTCAGCC-3'; 18S F 5'-GCTGCTGGCACCAGACTT-3', R 5'-CGGCTACCACATCCAAGG-3', probe 5'-CAAATTACCCACTCCCGACCCG-3'. All results are normalized to GAPDH mRNA and 18S ribosomal RNA internal controls and are expressed in relative numbers.

Affymetrix analysis

Total RNA from pcDNA-HA and HA-Monarch-1 HeLa stable clones was prepared using RNeasy Mini columns (Qiagen). Ten micrograms of RNA were reverse-transcribed using Superscript II (Stratagene, La Jolla, CA), labeled using the Enzo Bioarray High Yield RNA Transcript Labeling kit (Enzo Diagnostics, New York, NY), and analyzed on HG U133A chips at the University of North Carolina Genomics Facility (Chapel Hill, NC) according to the Affymetrix technical manual (http://www.affymetrix.com). Sample quality was assessed by examining 3'-5' intensity ratios of control genes. Arrays were scaled to an average intensity of 2500, and expression data were analyzed using GeneSpring software (Silicon Genetics, Redwood City, CA). Altered genes were identified by filtering for increase or decrease in all three Monarch-1-expressing clones compared with their respective control clone of 1.4-fold or more, with a minimum hybridization signal of 500 in the higher expressed sample. Values of p were determined using Affymetrix suite 5.0 (Santa Clara, CA).

Cytometric fluorometric analysis of HLA

Flow cytometry was performed as previously described (13). FITC-conjugated human pan-reactive HLA Ab (Caltag Laboratories, Burlingame, CA) and control FITC mouse IgG2a {kappa} isotype Ab (BD PharMingen, San Diego, CA) were used.

siRNA construction and transfection

Wild-type and mutant human Monarch-1 short hairpin RNAs were stably expressed in the human U937 monocyte cell line by transfection of plasmids containing short hairpin RNA transcription cassettes followed by clonal selection in puromycin as described.4 The targeted sequence is GTCCATGCTGGCACACAAG and the mutant sequence is GTCCATGCTAACACACAAG.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Identification of the human Monarch-1 cDNA

Previously, we identified genes for novel NBD/LRR proteins with structural similarities to CIITA via searches of the published Celera and the National Center for Biotechnology Information human genome databases (1). One of the predicted new genes, Monarch-1, was cloned by RT-PCR using primer pairs specific for both the suspected N- and C-terminal regions of the gene. The 5' end of the longest clone was isolated using RACE-PCR of cDNA from U937 cells. The full-length cDNA is 3731-bp long with a 220-bp 5' UTR, a 323-bp 3' UTR and a 3189-bp open reading frame (accession number AY116204,5 supplemental Fig. 1A6). Monarch-1 is located on human chromosome 19q13.4. Comparison with known mRNAs in the database revealed the 3' one-third of this gene was previously identified as RNO2 (14). During the preparation of this manuscript, the sequence for a new gene PYPAF7, has been published and is identical to isoform I of Monarch-1 except for an arginine deletion at aa 692 in PYPAF7 (3). Analysis of additional clones led to the isolation of a form missing aa 692 (PYPAF7). The Monarch-1 cDNA, contained in 10 exons, encodes a predicted protein of 1063 aa with a predicted molecular mass of 118 kDa (supplemental Fig. 1B). To investigate whether multiple Monarch-1 splice forms exist, PBMC total RNA was subjected to RT-PCR with primers spanning the end of the NBD through the C-terminal LRR region of Monarch-1 (not shown). At least four splice forms of the Monarch-1 LRR region are evident. Sequence analysis of the four prominent bands shows that these novel splice forms correspond to differential splicing of the LRR (accession numbers AY116205, AY116206, and AY116207) (supplemental Fig. 1, C, E, and G). The full-length Monarch-1 contains 10 exons (isoform I) while the shorter forms lack exon 9 (isoform II) (supplemental Fig. 1D), exons 7 and 8, (isoform III) (supplemental Fig. 1F), and exons 7 through 9 (isoform IV) (supplemental Fig. 1H), respectively. Analysis of Monarch-1 using RT-PCR with primers specific for the N-terminal region suggests that alternative N-terminal splice forms do not exist (not shown).



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  		FIGURE 1. Expression of Monarch-1 mRNA. A, Monarch-1 expression in separated human PBMC populations determined by RT-PCR. B, Monarch-1 expression in separated human myeloid cell populations, determined by real-time PCR. C, Monarch-1 expression in primary adherent cells after stimulation with DETA-NO, with TNF-{alpha} or IFN-{gamma} alone, or in combination as determined by real-time PCR. Monarch-1 expression was normalized to the expression of 18S ribosomal RNA. The Student t test was performed on control compared with treated cells (*, p < 0.01; +, p < 0.05). Three separate cell preparations were used and tested.

 
Expression of Monarch-1 is predominantly in myeloid-monocytic cells

RT-PCR shows expression in U937 and HL-60 cells but not T/B or nonhemopoietic cell lines (not shown). To assess Monarch-1 expression in PBMC subpopulations RT-PCR was performed, and showed expression in dendritic cells, monocytes, and granulocytes (Fig. 1A). A faint band was detected in the lymphocyte preparation, however this may be due to contamination as these same preparations show a faint band for the myeloid genes, CD14 and CD15. To more definitively compare Monarch-1 expression among the myeloid-monocytic cells, real-time PCR analysis was used (Fig. 1B). High levels of Monarch-1 were detected in granulocytes, with lower expression observed in monocytes. An increase in Monarch-1 expression is observed in monocytes in response to DETA-NO (an activator of nitric oxide) consistent with previous findings of nitric oxide induction of RNO2 mRNA expression (Fig. 1C) (14). In contrast, TNF-{alpha}, IFN-{gamma}, or a combination of the two decreased Monarch-1 expression in a time-dependent fashion.

Identification of Monarch-1-regulated genes by DNA microarray

To determine the downstream effects of increased Monarch-1, an Affymetrix DNA array analysis was performed to compare gene profiles in the presence or absence of Monarch-1. Stable clones expressing Monarch-1 were made in the HeLa cell line because these cells do not express Monarch-1 (Fig. 2A). Two sets of stable-expressing Monarch-1 clones were independently produced on different days by transfection of HeLa cells with either the empty vector control, pcDNA, or with a pcDNA-HA-tagged Monarch-1 expression vector and selected for neomycin resistance. The first experiment resulted in two Monarch-1-containing clones, clone A with lower Monarch-1 expression and clone B with higher expression. The second experiment resulted in one clone, C, with intermediate expression. Analysis of the Monarch-1 expression level in different RNA preparations of these clones relative to total primary human PBMCs indicates that the clones express lower levels of Monarch-1 than PBMCs. Thus changes detected in Monarch-1-expressing lines are likely to be relevant, and not due to the overexpression of Monarch-1. Clones with a higher Monarch-1 level were not obtained perhaps due to toxicity.



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  		FIGURE 2. Characterization of Monarch-1-regulated genes. A, Monarch-1 expression in HeLa lines stably transfected with Monarch-1 as determined by real-time PCR. Monarch-1 expression in total PBMCs was included for comparison. The level of Monarch-1 expression was normalized to the expression of GAPDH. The Student t test was performed on controls compared with stable transfected clones (*, p < 0.01). B, Affymetrix analysis of MHC-I-related genes induced in stable Monarch-1-expressing HeLa clones. Fold induction for each clone is calculated relative to its control clone. "x" indicates genes identified in the original analysis. Values of p were determined using Affymetrix suite 5.0 (*, p < 0.01; +, p < 0.05).

 
DNA microarray analysis was performed for control and Monarch-1-expressing stable clones using Affymetrix chips comprising ~22,000 gene sequences. The most prominent change is a cluster of nine MHC-I-related sequences, including HLA-B (three sequences), HLA-C (two sequences), HLA-F (one sequence), HLA-G (two sequences), and the proteosomal subunit LMP7 required for processing of class I peptides (samples with "x", Fig. 2B). The appearance of HLA-B, C, and G each multiple times further attests to the validity of these findings. Regulation of MHC-II genes by Monarch-1 was not observed (not shown). To assess whether additional MHC-I genes may be modulated by Monarch-1 but not included due to the stringent cutoff standards used for filtering, we examined the expression patterns of all HLA genes. All classical MHC-I (HLA-A, B, and C) and nonclassical MHC-I genes (HLA-E, F, and G) were up-regulated by Monarch-1.

To quantify the changes, real-time PCR was performed using total RNA isolated from A, B, and C stable clones. The levels of HLA-B, HLA-G, and LMP7 mRNA are enhanced in the Monarch-1 stable clones compared with controls (Fig. 3A). FACS analysis further confirmed up-regulation of MHC-I Ag (Fig. 3B). To discern the involvement of transcriptional or posttranscriptional mechanisms, we transiently cotransfected a Monarch-1 expression plasmid (or a control plasmid) with a luciferase reporter driven by 220 bp of the HLA-B promoter (15) in HeLa cells (Fig. 3C). Monarch-1 enhanced the HLA-B promoter >25 times. This enhanced activity over that seen for mRNA and protein levels may be due to transient transfection resulting in higher than physiological levels of Monarch-1.



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  		FIGURE 3. Monarch-1 enhances MHC-I and LMP-7 expression. A, Analysis of selected Monarch-1-regulated genes as determined by real-time PCR. Expression was normalized to the expression of 18S ribosomal RNA and shown as an exponential number. The Student t test was performed on controls compared with stable transfected clones (*, p < 0.01; +, p < 0.05). B, Human HLA surface expression on each of the Monarch-1 stable HeLa clones as determined by FACS analysis. In each graph, expression was compared with unstained (dotted line) and isotype control (thin line). Mean fluorescence intensity is displayed for each sample. C, Monarch-1 activates the HLA-B promoter-luciferase construct. Error bars represent the SEM of five separate experiments. The Student t test was performed on control compared with transfected clones (*, p < 0.01; +, p < 0.05).

 
Although the level of expression in the stable clones was less than that in primary blood cells and hence does not represent an overexpression system, the physiologic relevance of HeLa cells could be questioned. PYPAF7/Monarch-1 can interact with apoptotic speck protein (3), which is not expressed in HeLa cells but is expressed in monocytic lines. To address the regulation of MHC genes in a more relevant system, siRNA technology was used to reduce endogenous Monarch-1 expression levels in U937 cells, which express Monarch-1 and apoptotic speck protein (16). A vector containing a siRNA specific for Monarch-1 or a mutant siRNA with two mutated nucleotides was introduced into U937 cells. The bulk culture which should have a mixture of cells containing or lacking Monarch-1-specific siRNA showed a decrease of overall Monarch-1 expression compared with cells with control siRNA (Fig. 4A). Clones were then isolated under selectable conditions. Monarch-1 expression was significantly decreased in Monarch siRNA clones, but not in the controls (Fig. 4B, top panel). The levels of Monarch-1, HLA-B, and HLA-G mRNA were correspondingly decreased in the presence of Monarch-1-specific siRNAs but not siRNA controls (Fig. 4B, middle and bottom panels). These data strongly indicate that Monarch-1 controls both classical and nonclassical MHC-I genes in a physiologically relevant cell type.



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  		FIGURE 4. Analysis of MHC-I gene regulation by Monarch-1 in monocytic lines. A, Analysis of Monarch-1, HLA-B, and HLA-G expression in Monarch-1 and mutant siRNA bulk cultures determined by real-time PCR. Expression was normalized to the expression of GAPDH mRNA and represented as fold over mutant control. B, Analysis of Monarch-1, HLA-B, and HLA-G expression in Monarch-1 siRNA clones as determined by real-time PCR. Three independent clones generated by stable transfection of the mutant siRNA are shown (represented as mut) and two independent clones generated by stable transfection of wild-type siRNA are shown (represented as siRNA). Expression was normalized to GAPDH. Data are represented as exponential numbers. The Student t test was performed on the average of the control mutant clones compared with siRNA clones (*, p < 0.01; + = p < 0.05).

 
This work describes a novel pyrin/NBD/LRR protein, Monarch-1, which is expressed primarily by myeloid-monocytic cells. A prominent downstream effect of Monarch-1 is induction of both classical and nonclassical MHC-I genes and LMP7. IFN-{gamma} and TNF-{alpha}, known inducers of class I molecules, decreased Monarch-1 expression. However, no significant alteration of MHC class I HLA-G gene expression was observed in Fig. 1C at these time points (not shown). At later time points, HLA-G expression was enhanced by these two cytokines (not shown). This indicates that Monarch-1 does not play a major role in the induction of MHC-I by TNF-{alpha} and IFN-{gamma}. We suggest that the transcription factors induced by these two cytokines, including NF-{kappa}B and STAT-1, provide sufficiently strong signals to induce MHC-I despite the down-regulation of Monarch-1. In addition it suggests that Monarch-1 represents a new pathway for MHC-I induction separate from the TNF-{alpha} and IFN-{gamma} pathway.

Induction of both classical and nonclassical molecules by Monarch-1 indicates that it is a novel global inducer of MHC-I. More impressively, the reduction of Monarch-1 by siRNA caused a corresponding and almost equal decrease of both classical and nonclassical MHC-I in the monocytic line, U937. This indicates that although Monarch-1 may not be required for MHC-I expression in all cells because cells without this gene still express MHC-I, it is clearly an important regulator of MHC-I in myeloid-monocytic cells.

The classical MHC-I molecules, HLA-A/B/C are expressed on almost all nucleated cells while the nonclassical MHC-I, HLA-E, -F and -G have a more diverse distribution. HLA-G is expressed by activated macrophages (17) and classically by trophoblasts (15), HLA-F by B cells (18), and HLA-E is ubiquitous in expression (19). A series of conserved upstream DNA sequences in the classical MHC-I promoter include the AP-1 site (20), the NF-{kappa}B site, the IFN regulatory factor (IRF) binding site, and the S-X-Y module shared with MHC-II promoters (15). In contrast, nonclassical MHC gene upstream elements exhibit nucleotide sequence variations, mutations, and deletions in these regions (21). It will be of significant interest to identify the Monarch-1 responsive regulatory DNA. The up-regulation of classical and nonclassical MHC-I genes may have broad immunologic implications for the development of both CTLs and NK cells (22). Future studies in gene deletion mice will provide further insight concerning the physiologic role of Monarch-1 in modulating CTL or NK responses in vivo.


   Acknowledgments
 
We thank R. Diz for assistance with flow cytometry, P. J. v. d. Elsen and S. J. P. Gobin for the HLA-B luciferase reporter, A. Wong for assistance with real-time PCR, K. McKinnon for cell preparation, and J. Brickey for critical reading of the manuscript.


   Footnotes
 
1 This work was supported by National Institutes of Health Grants 29564, 45580, 41751, DK38108 and a National Institutes of Health postdoctoral training grant from the Lineberger Cancer Center. Back

2 Address correspondence and reprint requests to Dr. Jenny P.-Y. Ting, Department of Microbiology-Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, CB7295, Chapel Hill, NC 27599. E-mail address: panyun{at}med.unc.edu Back

3 Abbreviations used in this paper: NBD, nucleotide-binding domain; LRR, leucine-rich repeat; CATERPILLER, caspase recruitment domain, transcription enhancer, r(purine)-binding, pyrin, lots of leucine repeats; MHC-II, MHC class II; DETA-NO, [(Z)-1-[2-(2-aminoehtyl)-N-(2-ammonioethyl)amino]diazen-1-um-1,2-diolate]; F, forward; R, reverse; MHC-I, MHC class I; HA, hemagglutinin; siRNA, small interference RNA; CIITA, class II transactivator. Back

4 A. Wong, W. Brickey, D. J. Taxman, H. van Deventer, W. Reed, J. Gao, P. Zheng, Y. Liu, K. McKinnon, and J. Ting. Plexin-A1: a novel target of CIITA in dendritic cells and importance in antigen presentation. Submitted for publication. Back

5 The nucleotide sequences have been submitted to the GenBank/European Bioinformatics Institute Data Bank with accession numbers AY116204, AY116205, AY116206, AY116207. Back

6 The on-line version of this article contains supplemental material. Back

Received for publication February 2, 2003. Accepted for publication April 9, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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