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

Abstract

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 35 kDa 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.

Gimap4 accelerates T-cell death

“…15,16,18 In addition, there are several indications for a function of Gimap family members in survival and proliferation in the mouse, [33][34][35][36] rat, [14][15][16][17]37,38 as well as human. 10,34,39,40 Specifically, there are indications for an antiapoptotic activity of rat 37 and human 34 Gimap5, mouse Gimap8, 35 as well as a survival function of mouse Gimap1 36 and Gimap3. 33 These data strongly argue for a role of Gimap proteins in controlling apoptotic processes and thereby the homeostasis within the lymphoid lineage.…”

Impaired Post-Thymic Development of Regulatory CD4+25+ T Cells Contributes to Diabetes Pathogenesis in BB Rats

“…Human Ian5 is predominantly expressed in the thymus, peripheral CD4 ϩ and CD8 ϩ T cells as well as monocytes but not in normal B cells. However, high levels of expression are observed in neoplasms of the B cell lineage (11). The subcellular localization of the human 35-kDa Ian5 protein is still controversial because one study provided evidence for its anchoring to the mitochondrial membrane through its hydrophobic C terminus while the other reported a centrosomal/Golgi/endoplasmic reticulum localization (10,11).…”

“…It was also identified by another group through an in silico search for novel members of the human Ian gene family (11). Human Ian5 is predominantly expressed in the thymus, peripheral CD4 ϩ and CD8 ϩ T cells as well as monocytes but not in normal B cells.…”

Structural basis of oligomerization in septin-like GTPase of immunity-associated protein 2 (GIMAP2)

“…Furthermore, GIMAPs belong to the most down-regulated proteins in anaplastic large cell lymphomas compared to the progenitor T cells (19). In contrast, overexpression of GIMAPs was implicated in certain types of leukemia (20) and lung cancer (21).…”