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.
References
- Sica, G.L. et al. (2001) Blood 97:2702.
- Locksley, R.M. et al. (2001) Cell 104:487.
- Baker, S.J. and E.P. Reddy (1998) Oncogene 17:3261.