hIan5: the human ortholog to the rat Ian4/Iddm1/lyp is a
new member of the Ian family that is overexpressed in
B-cell lymphoid malignancies
T Zenz1, A Roessner1, A Thomas2, S Fro ¨hling1, H Do ¨hner1, B Calabretta3and L Dahe ´ron4
1Department of Medicine III, University Hospital Ulm, Ulm, Germany;2Department of Medicine I, University Hospital Freiburg,
Freiburg, Germany;3Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia,
PA, USA;4Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, USA
The family of immune associated nucleotide binding proteins (Ian) is a distinct family of GTP-binding proteins conserved in
plants, mice, rats and humans that are associated with immune functions, suggesting involvement in conserved defense
mechanisms. Recently, the rat Ian4 (rIan4) was cloned and it appears to be identical to the gene Iddm1/lyp responsible for
severe lymphopenia and the development of insulin-dependent diabetes in the BB-DP rat. Here we describe the
characterization of a new human member of the Ian family: hIan5. hIan5 is highly homologous to rIan4, has a predicted
molecular weight of 35kDa and contains distinct G motifs of GTP-binding proteins (G-1 to G-4) in the N-terminus. Human Ian5
is anchored to the mitochondria by the hydrophobic COOH-terminal domain. Human Ian5 is highly expressed in lymph node
and spleen. Different blood fractions show high hIan5 expression in CD4- and CD8-positive T cells and monocytes, but not in B
lymphocytes. In contrast, in B-CLL (chronic lymphocytic leukemia) and mantle cell lymphoma samples, hIan5 mRNA was
upregulated. The current data underline the role of hIan5 in T-lymphocyte development and function, and for the first time
suggest that upregulation of Ian proteins is associated with B-cell malignancy, possibly by inhibiting apoptosis.
Genes and Immunity (2004) 5, 109–116. doi:10.1038/sj.gene.6364044
Published online 15 January 2004
Keywords: chromosome 7q36; GTP binding; mitochondria; Ian family
Studies of receptors and signal transduction components
that play a role in plant disease resistance have revealed
remarkable similarities with innate immunity pathways
in mammals. This includes protein motifs and similar
signaling components (eg TOLL receptors).1,2
example of a conserved protein family in plants, mice,
rats and humans, which is associated with functions
within the immune system, is the recently discovered
family of immune-associated nucleotide-binding pro-
teins (Ian). The first Ian family members aig 1 and 2 are
genes induced by bacterial infection in Arabidopsis
thaliana.3,4The induction pattern of the aig genes
correlates with distinct defense responses.3,4There are
at least 11 murine proteins that belong to the Ian family,
all of which are clustered in a 150kb region on mouse
chromosome 6 (Mmu6). mIan1 is a thymic selection
marker expressed in CD4þ and CD8þ T cells.5mIan4
has been shown to encode a mitochondrial GTP-binding
protein induced by the BCR/ABL oncogene. It is
normally expressed in lymph node and spleen.6IMAP38
(immunity-associated protein 38), an additional family
member, was cloned as a differentially expressed gene
induced by Plasmodium chabaudi infection in a mouse
malaria model.7,8Thus far, the most conclusive data
on the important role of the Ian family within the
immune system come from studies of a rat model for
insulin-dependent diabetes mellitus (IDDM) type I.
Diabetes-prone (DP) BB rats spontaneously develop
insulin-dependent diabetes resembling human type I
diabetes.9,10The rats also exhibit lifelong T-cell lympho-
penia. Functional and genetic data support the hypoth-
esis that the gene responsible for the lymphopenia, Lyp,
is also a diabetes susceptibility gene, named Iddm1. Two
separate groups mapped the locus for lyp on rat
chromosome 4 and found a frameshift mutation in one
gene within this locus, rIan4 (named rIan5 by MacMur-
ray et al) among lymphopenic rats.9,10The mutation
results in a truncated protein in which the COOH-
terminal 215 amino acids are replaced by 19 other amino
acids.9,10Very recently, Pandarpurkar et al11found that
lymphocytes lacking rIan4 have a defect in mitochon-
drial integrity and substantially increased propensity to
undergo apoptosis. In humans, three Ian members have
been characterized so far: the HIMAP1 (human immu-
nity-associated protein 1/hIan2) 34kDa protein is loca-
lized at the endoplasmic reticulum (ER).12It contains a
GTP-binding domain and is highly similar to the other
known Ian family members. The himap1 gene is
predominantly expressed in the spleen and to a lesser
extent in lymph nodes. Cambot et al13recently cloned the
Received 11 July 2003; revised 23 October 2003; accepted 31 October
Correspondence: T Zenz, Department of Medicine III, University Hospital
Ulm, Robert-Koch-Str. 8, 89081 Ulm, Germany.
Genes and Immunity (2004) 5, 109–116
& 2004 Nature Publishing Group All rights reserved 1466-4879/04 $25.00
14 Sandal T, Aumo L, Hedin L, Gjertsen BT, Doskeland SO. Irod/
Ian5: an inhibitor of gamma-radiation- and okadaic acid-
induced apoptosis. Mol Biol Cell 2003; 14: 3292–3304.
15 Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic
local alignment search tool. J Mol Biol 1990; 215: 403–410.
16 Walker JE, Saraste M, Runswick MJ, Gay NJ. Distantly related
sequences in the alpha- and beta-subunits of ATP synthase,
myosin, kinases and other ATP-requiring enzymes and a
common nucleotide binding fold. EMBO J 1982; 1: 945–951.
17 Dohner K, Brown J, Hehmann U et al. Molecular cytogenetic
characterization of a critical region in bands 7q35–36 com-
monly deleted in malignant myeloid disorders. Blood 1998; 92:
18 Cserzo M, Wallin E, Simon I, von Heijne G, Elofsson A.
Prediction of transmembrane alpha-helices in procariotic
membrane proteins: the dense alignment surface method.
Prot Eng 1997; 10: 673–676.
19 Viardot A, Moller P, Hogel J et al. Clinicopathologic correla-
tions of genomic gains and losses in follicular lymphoma.
J Clin Oncol 2002; 20: 4523–4530.
20 Hales KG, Fuller MT. Developmentally regulated mitochon-
drial fusion mediated by a conserved, novel, predicted
GTPase. Cell 1997; 90: 121–129.
21 Santel A, Fuller MT. Control of mitochondrial morphology by
a human mitofusin. J Cell Sci 2001; 114: 867–874.
22 Thomson M. What are guanosine triphosphate-binding
proteins doing in mitochondria? Biochim Biophys Acta 1998;
23 Kessler F, Blobel G, Patel HV, Schnell DJ. Identification of two
GTP-binding proteins in the chloroplast protein import
machinery. Science 1994; 266: 1035–1039.
24 Schneider E, Hunke S. ATP binding cassette (ABC) transport
systems: functional and structuralaaspects of the ATP-
hydrolyzing subunits/domains. FEMS Microbiol Rev 1998;
25 Hogue DL, Liu L, Ling V. Identification and characterization
of a mammalian mitochondrial ATP-binding cassette mem-
brane protein. J Mol Biol 1999; 285: 379–389.
26 Castedo M, Kroemer G. The beauty of death. Trends Cell Biol
2002; 12: 446.
27 Iwakoshi NN, Goldschneider I, Tausche F, Mordes JP,
Rossini AA, Greiner DL. High frequency apoptosis of recent
thymic emigrants in the liver of lymphopenic diabetes-prone
BioBreeding rats. J Immunol 1998; 160: 5838–5850.
28 Schattner EJ. Apoptosis in lymphocytic leukemias and
lymphomas. Cancer Invest 2002; 20: 737–748.
Role of hIan5
T Zenz et al
Genes and Immunity