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Cutting Edge |
Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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CIITA was isolated using a complementation cloning strategy to restore
MHC II expression to a MHC II-deficient cell line (1).
CIITA is a master regulator of transcription, responsible for both
IFN-
and constitutive expression of MHC II and related genes
(8, 9). The N-terminal activation domain of CIITA is
necessary for transcriptional activation (8). The
centrally located NBD of CIITA contains a GTP-binding domain required
for nuclear import (8). CIITA undergoes self-association
involving sequences in its NBD, C-terminal LRRs, and N terminus
(10).
When CIITA was first discovered, initial searches for CIITA-related
genes produced no significant matches. Nod1, an activator of
caspase-9-mediated apoptosis and NF-
B, also having an NBD
and C-terminal LRRs, was the first described protein similar to CIITA
in domain organization (11, 12). Nod2, with functions
similar to those of Nod1, has been strongly implicated in Crohn’s
disease (2, 3, 13) and in familial granulomatous synovitis
(Blau syndrome) (14). Most recently, patients with
familial cold autoinflammatory syndrome (familial cold urticaria) and
Muckle-Wells syndrome were found to have mutations in a new gene called
CIAS1, which has a pyrin domain, NBD, and LRR
(4). These syndromes are associated with a
CIAS1 splice variant called cryopyrin. These proteins may be
similar to plant disease resistance proteins (R proteins) which detect
pathogens and initiate defense mechanisms including MAP kinase
activation, oxygen radical formation, salicylate production, induced
transcription of kinases and transcription factors, and rapid cell
death (15). Many of these plant proteins have an NBD and
LRRs and may represent the oldest examples of proteins using this
CIITA-like domain arrangement.
The advent of the nearly complete human genome sequence facilitated a search for sequences related to these proteins. We describe the identification of additional putative mammalian NBD/LRR proteins similar to the known family members. Including those already known, this analysis predicts at least 22 NBD/LRR genes in the human genome, which we call the CATERPILLER (CARD, transcription enhancer, R(purine)-binding, pyrin, lots of leucine repeats) gene family. Determination of chromosomal location, genomic organization, and sequence information are also shown.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Searches were performed using the published Celera human genome
scaffold data (16), the National Center for Biotechnology
Information (NCBI) "nr" database (containing GenBank, European
Molecular Biology Laboratory, DNA Data Base in Japan, Protein Data
Base, and completed phase 3 and 4 high-throughput genomic sequencing
(HTGS) sequences), and the NCBI genome database, (17).
Initial searches were performed using the B cell form of CIITA protein
sequence (1) as a query using the BLAST search algorithms
BLASTP and TBLASTN (see supplemental data Fig. 1
).5 BLASTP identifies amino
acid sequence similarities through query sequence comparison with
database proteins and is more likely to find distant relationships than
BLASTN (18). TBLASTN compares the query protein sequence
with translations of all six reading frames of available nucleotide
sequences and has the same advantages as BLASTP. We used analogous
domains of the resultant sequences to identify additional sequences
and/or confirm initial identities; this is known as DOUBLE-BLAST,
inspired by the intermediate search sequence method of Park et
al. (19, 20) and is comparable in homologue detection with
Hidden Markov Methods. LRR sequences, the N-terminal pyrin domains of
DEFCAP, and the CARD domains of Nod1 and Nod2 were used to perform
similar searches. The N-terminal sequences of CIITA yielded no related
sequences obviously belonging to an NBD/LRR protein.
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Pyrin and LRR sequences identified within contigs containing NBDs were examined for location and orientation to determine the likelihood of residing in the same operon as an identified NBD. Pyrin and LRR domains were considered contiguous with an NBD if they fell upstream and downstream of the NBD, respectively, in the same orientation. CARD domains occur both upstream (Nod1/2) and downstream (DEFCAP) of the NBD (21), but none of the novel sequences contained CARD domains. As sequence data became available for more than a single domain, a putative genomic organization was generated by comparing the cDNA sequence with the genome sequence.
Cell lines, preparation of RNA, and RT-PCR
HeLa, MCF7, Jurkat, RAJI, and RAMOS cell lines were cultured in either DMEM (high glucose) or RPMI 1640 with 10% FCS, L-glutamine, and penicillin/streptomycin. Peripheral blood leukocytes were obtained as buffy coats from the American Red Cross (Durham, NC). Total RNA was prepared using the SV Total RNA Isolation kit (Promega, Madison, WI). Total RNA was reversed transcribed to cDNA using Moloney murine leukemia virus reverse transcriptase and amplified in an MJ Thermocycler (MJ Research, Cambridge, MA) in a separate reaction with primers specific for each target sequence. Amplification products were electrophoresed on 0.8% agarose and visualized with ethidium bromide.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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BLAST searches of the published Celera and NCBI genomic
databases using the NBD and LRR of CIITA, Nod1, Nod2,
DEFCAP, and resultant target sequences as queries revealed 22
potential genes and pseudogenes, including the presently known genes,
unified by the presence of an NBD and downstream LRRs (Table I). New genes were assigned a name based
on chromosome number and order of discovery (e.g., 19.1, first
found on chromosome 19). Nod1, Nod2, and DEFCAP contain CARD domains
that may be involved in recruiting caspases (12, 13, 21).
DEFCAP also has an N-terminal pyrin domain with homology to the
familial Mediterranean fever protein (7). BLAST searches
were also performed for the CARD domains of Nod1/2, the pyrin domain of
DEFCAP, and resulting target sequences. CARD domain homologues were not
found for any of the novel sequences. The majority of the putative
genes have upstream pyrin domains, but the upstream N-terminal
sequences of several remain unknown.
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We determined exon/intron sizes and positions for the known and
some predicted NBD/LRR proteins by the location of the sequence
corresponding to the mRNA/cDNA assuming intactness of the contig (Fig. 1
A). The genomic organization
is complex and remarkably similar for all the sequences examined, with
large NBD exons (
1500 nt) and LRR exons of 76 nt, 174 nt, or both
depending of the gene. CARD and pyrin domains are 300 nt
long.
CATERPILLER domains
Table I highlights the distinct domains of each sequence. Nod1,
Nod2, and CIITA have N-terminal CARD or CARD-like domains. Thirteen
have N-terminal pyrin domains. CIITA is unique in having an N-terminal
acidic trans activation domain. Five of these sequences do
not have CARD, pyrin, or CIITA-like activation domains upstream of
their NBDs. The diversity of these N-terminal sequences suggests
multiple functional modes.
The predicted nucleotide specificity based on motifs found in the
CATERPILLER genes is shown in Table I. This is compared with another
family, containing plant and animal proteins, grouped on the basis of a
NTPase domain and C-terminal repeats of either the LRR or WD40 type,
called the NACHT family, which includes NAIP, CIITA, HET-E, and TP1
(22). Remarkably, the majority are predicted to
be ATP-binding proteins, with the exception of CIITA, which binds GTP,
and HET-E. A GTP-binding protein-like magnesium coordination (G3) motif
(DXXG) occurs in a number of the other sequences, but excepting the
more distantly related Apaf1, it follows the more typical kinase 2 site
found in ATP-binding proteins.
We aligned the NBDs of these predicted proteins, each 500 aa long,
and observed 12 groupings of conserved residues (motifs) (Fig. 1B). The full protein alignment of the NBD domains is shown
in supplemental data Fig. 2. Although the seven NACHT motifs are
present, the larger number of compared sequences permits a refined
definition of the NACHT domain that excludes WD40 repeat-containing
members, thus distinguishing a CATERPILLER NBD from the broader NACHT
family. These motif definitions also suggest a divergence between the
majority of the NBDs that we describe and those like NAIP. Functionally
important motifs likely include motif I, which contains the Walker A
sequence found in most nucleotide-binding proteins (23),
and motifs III and V that overlap or are adjacent to leucine-charged
domain motifs (24). These motifs are important for CIITA
function (8). Motif III contains the kinase 2 motif which
coordinates magnesium ions in ATP-binding proteins
(23).
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74 nt) containing one
motif iteration or a duplex (180 nt) containing two (Table I (column
8), Fig. 1A, and supplemental data Fig. 3). The sole
absolute requirement for inclusion as an LRR is conservation of the
hydrophobic residues "leucines" comprising the motif. BLAST
searches for LRRs may miss some sequences due to a greater likelihood
of less similarity between non-LRR-motif residues. Thus, without actual
cDNA clones, it is impossible to be highly confident that all of the
LRR exons downstream of the NBD have been identified for each putative
gene. Given this caveat, it appears that all of the genes on chromosome
19 have doublet LRR exons whereas those on chromosome 16 have singlets.
DEFCAP and the potential pseudogene 12 have both singlet and doublet
exons. Phylogenetic analysis of the NBD and evolutionary issues
An analysis using protein alignment and tree generation software
(Data Analysis in Molecular Biology and Evolution) (25)
was performed to examine the potential phylogenetic relationship of the
predicted NBD protein sequences (Fig. 2A). Apaf1 and RPM1 (Table I)
were included because their NBD regions are similar to those of this
family. Except for 11.3, the newly identified NBD sequences are more
closely related to one another than Apaf1 (Fig. 2A),
suggesting that NBD/WD40 repeat proteins are more distantly related.
Interestingly, the NBD of RPM1, an NBD/LRR R protein of
Arabadopsis, is most closely related to Apaf1. The novel NBD
most closely related to RPM1 is 11.3 which has an NBD exon interrupted
by an intron. Consistent with divergent evolution, the NBDs of the
known and putative proteins with upstream CARD domains are more closely
related to each other than to those NBDs with upstream pyrin domains
which form their own grouping phylogenetically. Further analysis of
NBD/LRR-type plant R proteins and other eukaryotic NBD/LRR proteins
will help resolve issues of divergent vs convergent evolution.
The assignment of the CATERPILLER genes to chromosomal positions is
shown in Fig. 2B. Most are found in clusters on chromosomes
11, 16, and 19. Three occur at 11p15, three more between 16p12 and
16p13, and nine at 19q13. Proximities of the six sequences on a single
contig at 19q13.4 strongly suggest that gene duplication has occurred
for these sequences. All except four of these sequences are near the
telomere, suggesting that those found singly may have their origins in
chromosomal recombination. Among those not at the telomeric end of
chromosomes, one (X) is likely a pseudogene. In
Saccharomyces, fermentation gene alleles are thought to have
been generated by the duplication of genes close to the telomeric end
and subsequent genomic dispersion by recombination (26).
Comparative genomics studies will best address these questions.
The presence of multiple individual exons containing one or two LRRs implies that exon shuffling may occur and that natural selection may favor the maintenance or elimination of a given LRR sequence or pair while simultaneously preserving other aspects of the gene in question (see supplemental data Figs. 3 and 4A). The specificity of plant R proteins is principally dependent on the LRR, and these are targets for diversifying selection (15). In Flax, a 6-aa difference in the LRR of P vs P2 determines Rust R protein specificity (27). The LRRs of RPS2 contain a small stretch important for cooperation with host factors determining Arabidopsis resistance to Pseudomonas syringae (28). Unequal recombination, gene conversion, and accumulated mutations likely generate novel specificities for the NBD/LRR class of R proteins.
Evidence for expression of the CATERPILLER genes
In light of these data, the NBD/LRR protein family is larger than
currently known. Significant information is available on the expression
patterns of the known genes and this reflects their biologic role.
CIITA has three different isoforms arising from three different
promoters. Nod1 has a wide tissue distribution (12),
whereas Nod2 and CIAS1 are restricted to monocytes, consistent with
inflammatory roles (4, 13). To begin to examine the
expression of the other sequences, we have used the NCBI database to
search for expressed sequence tags encoding at least part of the
sequence (see Table II). UniGene sequence entries exist for
CIAS1, Nod1, Nod2, DEFCAP,
Nalp2, and 16.1. Fourteen of the genes are represented in
GenBank human expressed sequence tag (est) database. The gene we
identify as 19.3 has been previously described as a partial cDNA
encoding a 344-aa protein (RNO2) composed of LRRs and is expressed in
bone marrow, peripheral blood leukocytes, and nitric oxide-treated
HL-60 cells (29). No est entry was found for 11.2, 12,
19.1, 19.2, 19.5, 19.8, or X. We have also conducted a preliminary
survey of the expression of these new genes, summarized in Table II, and have detected message for
every nonpseudogene except 19.1 and 19.2. Nearly all of the family
members are expressed in hemopoietic cells and are likely restricted in
that ubiquitous expression was uncommon.
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Of the known genes, CIITA, CIAS1, and Nod2
are clearly linked to immune function. CIITA directly controls MHC II
gene expression, whereas CIAS1 in familial cold urticaria and Nod2 in
Crohn’s disease are likely regulating inflammatory responses. DEFCAP
and Nod1 both promote apoptosis and activate NF-B.
Activation of NF-B is also observed for Nod2, and under appropriate
conditions for CIAS1. These functions are reminiscent of plant R
proteins that promote plant responses similar to innate immune
functions (15).
Innate immune responses mediated by Toll in response to fungal pathogens in Drosophila highlight the importance of receptors recognizing specific pathogen-associated molecular patterns (30). LRR-containing proteins in plants and animals serve a similar function; this contention is supported by our threading result with selected LRRs suggesting that LRR structural features are conserved in the NBD/LRR family (supplemental data Fig. 4). Toll-like receptors have extracellular LRRs mediating recognition of a variety of microbial derivatives (31, 32). The LRRs of plant R proteins likewise recognize avirulence proteins from plant pathogens and provide specificity (33). Recent studies of Nod1 and Nod2 demonstrate that both require their LRRs for responses to various bacterial LPS (34). The LRRs of CIITA (although not known to interact with any pathogen-specific molecule) are functionally necessary, are involved in self-association and interaction with an endogenous protein, and regulate nuclear import (10). Thus, these LRRs likely serve as versatile recognition domains with specificity for self-interaction, protein/lipid/sugar recognition, or both, which seems probable. Deletion of the LRRs from Nod1/2, DEFCAP, and CIAS1 enhances their activities, suggesting that these LRRs are important sites of regulation.
As further evidence of the immunologic relatedness of this family of gene, we have recently studied the 19.3 gene product (named Monarch-1) and found it to be predominantly expressed by cells of the myeloid-monocytic-dendritic lineage. In addition, 19.3 expression is dramatically altered by bacterial products, and influences a number of immunologically relevant events.6
Related issues
The number of mammalian NBD/LRR sequences we were able to identify is significantly smaller than that occurring in some plants (35). The mammalian family may be larger than we describe as NAIP and Ipaf (CARD12), despite having NBDs and LRRs, were not detected using our parameters (except when using 16.2), likely due to the absence of some of the CATERPILLER motifs in their NBDs. Limited BLAST searches of translated nucleotide sequences from Drosophila and Caenorhabditis elegans, genomic databases failed to identify any NBD/LRR genes. A similar search of the Danio rerio (zebrafish) database did yield likely NBD/LRR sequences, and the mouse genome has at least as many genes in this family as did humans (J. A. Harton, unpublished observation). The preponderance of NBD/LRR proteins in plants is due to reliance on individual effector molecules for recognizing pathogen-specific products. Higher order eukaryotes have developed a highly complex adaptive immune system driving a staggering array of protein-specific immune responses with a limited number of genes.
N-terminal variation in the known and predicted genes suggests a
subdivision of CATERPILLER proteins: group I, CARD-containing (e.g.,
Nod1); group II, pyrin-containing (e.g., DEFCAP); group III,
trans activation domain (e.g., CIITA); and unknown (e.g.,
16.1) (see Table I). However, these grouping may be oversimplified. For
example, multiple cell type-specific forms of CIITA are known. The
dendritic cell form has a CARD-like N terminus followed by the
activation domain, although no caspase recruitment activity has been
described (36). It is of interest that Nod2 and
cryopyrin are also expressed as multiple transcripts (4, 13). Whether these different transcripts code for proteins of
somewhat different function is clearly of interest. Additionally,
self-association has also been demonstrated for CIITA and Nod1, whereas
heterodimerization of CIAS1 with apoptotic protein ASC may involve the
pyrin domain of CIAS1 (5, 10, 12). Self- and
heteroassociation might amplify and generate diversity necessary to
mediate appropriate responses.
Genes coding proteins structurally related to CIITA, Nod2, and others in having an NBD, multiple C-terminal LRRs, and few different N-terminal domains abound in the human genome. The sequences and genomic organization of these genes suggest a high degree of relatedness, a common origin, and a potential link to the basic immune response genes of plants. Studies on CIITA, CIAS1, DEFCAP, Nod1, and Nod2 reveal some interesting parallels with the plant proteins and strongly suggest that this family of proteins will likely influence mammalian immune responses.
Note added in proof. During the review of this manuscript a report describing the initial characterization of Pypaf7, which we refer to as 19.3/Monarch-1, was published. 2002, J. Biol. Chem. 277:29874.
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Footnotes |
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2 J.A.H. and M.W.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Jenny P.-Y. Ting, Campus Box 7295, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599-7295. E-mail address: panyun{at}med.unc.edu
4 Abbreviations used in this paper: NBD, nucleotide-binding domain; LRR, leucine-rich repeat; est, expressed sequence tag; CATERPILLER, CARD, transcription enhancer, R (purine)-binding, pyrin, lots of leucine repeats.
5 The on-line version of this article contains supplemental material.
6 K. L. Williams, D. J. Taxman, M. W. Linhoff, and J. P.-Y. Ting. Monarch-1: a Pyrin/NBD/LRR protein that broadly controls classical and non-classical class I MHC genes. Submitted for publication.
Received for publication July 23, 2002. Accepted for publication August 22, 2002.
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B. J. Conti, B. K. Davis, J. Zhang, W. O'Connor Jr., K. L. Williams, and J. P.-Y. Ting CATERPILLER 16.2 (CLR16.2), a Novel NBD/LRR Family Member That Negatively Regulates T Cell Function J. Biol. Chem., May 6, 2005; 280(18): 18375 - 18385. [Abstract] [Full Text] [PDF]
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