RELT (Receptor Expressed in Lymphoid Tissues) is the most recently identified member of the tumor necrosis factor receptor superfamily (TNFRSF) and shows distinct, feature characteristics of this receptor group.1 For example, RELT is a type I transmembrane glycoprotein with canonical cysteine rich domains and activates the NF-kappa B signaling pathway. Only the extracellular domain of RELT shows sequence homology to other members of the TNFRSF, however, while the intracellular domain shows no sequence homology to other published sequences. These features of RELT identify this gene as a novel member of the TNFRSF.2, 3
RELT mRNA, approximately a 2.6 kb transcript, is highly expressed in several tissues including spleen, bone marrow, peripheral blood leukocytes, and lymph node, as well as in immune cell-derived lines. Low or no expression of RELT has been found in other tissue types such as skeletal muscle, testis, brain, heart, placenta, lung, kidney, and pancreas. This expression pattern suggests that RELT plays a role specific in hematological tissues and immune cells. Other lines of evidence that indicate a functional role for RELT in immune cells are the observations that RELT can bind activated T cells and that it costimulates T cell proliferation in the presence of CD3.
Since other TNFRSF members utilize the TNF Receptor Associated Factors (TRAFs) for NF-kappa B activation, studies were undertaken to determine if RELT signal transduction also depended on the TRAFs. Interestingly, RELT was shown to exclusively bind TRAF1, making this receptor unique within the TNFRSF. Binding of TRAF1 to RELT, however, does not necessarily lead to NF-kappa B activation. This conclusion can be drawn since NF-kappa B activation can occur in 293 cells transfected with RELT, yet these cells do not express TRAF1. This data indicates that even though RELT can bind TRAF1, TRAF1 may not exclusively transmit the signal for NF-kappa B activation. Other evidence for the fact that the TRAF family of molecules does not participate in the signal transduction from RELT for NF-kappa B activation is from an experiment with a dominant negative form of TRAF2 (TRAF2DM). When RELT and TRAF2DM are co-transfected into 293 cells, NF-kappa B activation is not altered. Therefore, NF-kappa B activation must not occur either directly with or through recruitment of TRAF2. While other TRAF molecules do not bind RELT, this does not preclude the possibility that these molecules may serve as accessory proteins for signal transduction.
In summary, RELT possesses many of the hallmark characteristics of the TNFRSF, including the cysteine rich domains in the extracellular region and the ability to activate NF-kappa B. Additionally, RELT is expressed in hematologically important tissues and potentially plays a role in T cell proliferation. Even though RELT is able to bind TRAF1, evidence points to an alternate pathway for NF-kappa B activation.