Elsevier

Gene

Volume 341, 27 October 2004, Pages 291-304
Gene

Comparative analysis of the human gimap gene cluster encoding a novel GTPase family

https://doi.org/10.1016/j.gene.2004.07.005Get rights and content

Abstract

There is a growing family of novel GTPases conserved among higher plants and vertebrates, abbreviated as AIG1, IAP, IMAP, and IAN, respectively. Here, we comparatively analyze the human gene family encoding GTPases of the immunity-associated protein family recently re-termed GIMAP. Chromosome 7q36.1 contains, within 300 kb, a gimap gene cluster with seven functional genes and one pseudogene (hgimap3). The six genes hgimap1, hgimap2, hgimap4, hgimap5, hgimap6, and hgimap7 encode 33–46 kDa proteins with one GTP-binding domain, whereas hgimap8 encodes a very unusual 75-kDa protein with three GTP-binding domains. All hgimap genes except hgimap2 have orthologs in the mouse. Major expression sites of hgimap mRNAs are the spleen and lymph nodes, but also other organs such as muscle, heart, placenta, and digestive tract display detectable hgimap mRNA levels. The proteins hGIMAP4 and hGIMAP7 can be localized at ER and Golgi apparatus, but not in mitochondria, lysosomes and nuclei. All hgimap genes were expressed at very low levels—if at all—in diverse cancer cell lines. Our data support the view that the GIMAP proteins are involved in the control of cell survival not only in cells of the immune system as commonly anticipated.

Introduction

GTP-binding proteins or GTPases are ubiquitously expressed and regulate a wide variety of different processes in cells. In recent years, several reports have described novel GTPases defining a new family specific for vertebrates and angiosperm plants (e.g. Poirier et al., 1999). These GTPases are not found in the well-characterized genomes of unicellular organisms such as Saccharomyces cerevisiae and Schizosaccharomyces pombe, or evertebrates including the model organisms Caenorhabditis elegans and Drosophila melanogaster. Current evidence, though still largely rudimentary, indicates that at least some of these small GTPases are critically associated with the outcome of diseases and the host defense against pathogens.

The genes encoding these small GTPases belong to a family which is evolutionary conserved among Arabidopsis, mouse, rat, and human. The plant prototype gene was found in Arabidopsis thaliana and designated as AIG1 for avrRpt2-induced gene (Reuber and Ausubel, 1996). AIG1 expression is induced by the virulent pathogenic bacterium Pseudomonas syringae. Rapid and transient induction of AIG1 occurs in an avirulent infection model associated with development of a protective hypersensitivity reaction, whereas virulent infections exhibit a delayed up-regulation of AIG1 (Reuber and Ausubel, 1996).

In mice, the prototype gene is imap38 which is induced by the experimental malaria Plasmodium chabaudi and its expression correlates with development of long-lasting immunity against homologous rechallenge (Krücken et al., 1997). Another member of this family in mice was described as mIAN-1 which is transiently induced in positively selected cells during T cell maturation in the thymus (Poirier et al., 1999). Recently, a novel member of this GTPase family (MacMurray et al., 2002) was described as rIAN5 in the BB rat. Its mutation results in T cell lymphopenia causing diabetes in this model. Another group designated this gene as rian4 (Hornum et al., 2002) because of its high similarity with the mouse gene mian4, which is induced in myeloma cells by overexpression of the BCR/Abl fusion oncogene (Dahéron et al., 2001).

The first prototype genes encoding members of this GTPase family in humans were described as himap1 (Stamm et al., 2002) and hian1 (Cambot et al., 2002). The himap1 gene, as its ortholog imap38 in the mouse, is predominantly expressed in the spleen. Like himap1, the hian1 gene is also preferentially expressed in the spleen. It appears to be important for the activation of T cells and B cells, as it is down-regulated at the protein level during activation of lymphocytes. In order to avoid confusion originating from different imap and ian designations for mouse and human genes and to adopt gene names conforming to the guidelines for human gene nomenclature (Wain et al., 2002), the human gene nomenclature committee has recently introduced the term GIMAP for GTPase of the immunity associated protein family. All human and mouse AIG1-like genes were designated according to the new nomenclature (Table 1) and these names will be used throughout this study. Our study comparatively analyses all members of the human gimap gene family in relation to the orthologous genes in mice.

Section snippets

Database screening and phylogenetic analysis

Using BLASTN (Altschul et al., 1990) and TBLASTN (Altschul et al., 1997), cDNA and EST entries corresponding to hgimap genes were identified in GenBank®. Deduced protein sequences were analyzed using GOR4 (Garnier et al., 1996), PSORTII (Nakai and Horton, 1999), Coils (Lupas et al., 1991), Mitoprot (Claros and Vincens, 1996), and InterProScan (Mulder et al., 2003). The phylogenetic analysis was performed only with the most conserved region of AIG1-like proteins, beginning with the first

Genomic arrangement and phylogenetic analysis of the human gimap gene cluster

The protein AIG1 from A. thaliana is the prototype member of a recently described GTPase family. The so-called AIG1 domain in the Pfam database (Bateman and Haft, 2002) (accession number PF04548) exhibits the five motifs G1–G5 (cf. Sprang, 1997) characteristic for GTP/GDP-binding proteins. In addition, the AIG1 domain contains a unique, highly conserved, hydrophobic motif between G3 and G4 (Fig. 1). The consensus sequence for this conserved box (=CB) has been deduced from the human GIMAP

Discussion

This study provides the first comparative analysis of all human gimap genes which are clustered on chromosome 7q36.1 and encode a novel GTPase family. Common to all GIMAP proteins is the so-called AIG1 domain which contains the five motifs G1–G5 characteristic for the GTP-binding site of GTPases in general and, additionally, a conserved, quite hydrophobic box between G3 and G4 unique to AIG1-like proteins. This box consists of L67S67xP78G89P78H89A67L56L78L100V100xQ56L89G100R78Θ100T100xE55Ψ100

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    The nucleotide sequences in this paper have been submitted to the GenBankEMBL with accession numbers AJ580951 and AJ580952.

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