Download Gene Section TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy)

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Gene Section
Review
TNFRSF6B (tumor necrosis factor receptor
superfamily, member 6b, decoy)
Jiangping Wu, Bing Han
CHUM Research Center, University of Montreal, Canada
Published in Atlas Database: December 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/TNFRSF6BID42628ch20q13.html
DOI: 10.4267/2042/38558
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology
molecular weight of 35 kD. Although TNFRSF6B
belongs to the TNFR superfamily, it lacks the
transmembrane and cytosolic domains in its sequence,
and is a secreted protein. It contains 4 TNFR cysteinrich regions, as illustrated above.
TNFRSF6B can be easily cleaved between Arg218 and
Ala219 in biological fluids and solutions. It has thus a
very short (about 20 min) half-life in serum and in
vivo. Mutation of arginine residue at position 218 to
glutamine makes TNFRSF6B resistant to proteolysis,
and significantly prolongs its half-life. TNFRSF6B can
bind to the TNF family members FasL, LIGHT and
TL1A. It does not bind to other known TNF family
members. Human TNFRSF6B can bind to mouse FasL,
LIGHT
and
TL1A.
This
allows
human
DcR3/TNFRSF6B to function in mouse models both in
vitro and in vivo. The role of TNFRSF6B in apoptosis
is obvious. FasL is a well-known molecule involved in
apoptosis. LIGHT is a ligand for HVEM and LTbetaR,
in addition to being a ligand for TNFRSF6B. LIGHT
can induce apoptosis in cells expressing both HVEM
and LTbetaR, or LTbetaR alone. TL1A, a member of
the TNF family, can evoke apoptosis via its receptor,
DR3. Consequently, the interaction of TNFRSF6B with
FasL, LIGHT, and TL1A blocks apoptosis mediated by
Fas, HVEM, LTbetaR and DR3.
Identity
Hugo: TNFRSF6B
Other names: DCR3 (decoy receptor 3);
DJ583P15.1.1; M68; TR6 (TNF receptor family
member 6)
Location: 20q13.3
DNA/RNA
Description
DNA sequence is located on chromosome 20.
Transcription consists of 7 exons and 6 introns,
spanning 3.6kb.
A shorter transcription variance (M68E) has been
identified, and is transcribed from 3 exons and 2 introns
spanning 1.9kb as illustrated above. The difference
occurs at the 5' untranslated region, but the two
transcripts encode the same isoform. Mice do not have
a gene orthologue to human TNFRSF6B.
TNFRSF68B mRNA in Northen blot presents as a 1.2knt band.
Protein
Description
TNFRSF6B protein is 300-amino acid long, and has a
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4)
334
TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy)
Wu J, Han B
A) Domains and Motifs. B) TNFRSF6B X-ray crystography.
apoptosis, it is thus can effectively inhibit apoptosis in
many cell types. It is believed that many types of
malignant tumors gain survival advantage by secreting
TNFRSF6B which blocks tumor cell apoptosis.
Syngeneic islets transplanted to diabetes recipients
survive better in the presence of administered
exogenous human TNFRSF6B, due to the blockage of
FasL-, LIGHT- and TL1A-triggered islets apoptosis.
Transgenic expression of human TNFRSF6B in NOD
mouse islets reduces diabetes pathogenesis, again, due
to anti-apoptotic effect of TNFRSF6B.
The forward signaling from FasL to Fas, and from
LIGHT to HVEM can provide costimulation signals to
resting T cells. Blocking of these two signaling
pathways reduces T cell responses to antigens. As
LIGHT and FasL, although being ligands, are also
transmembrane proteins, and are capable of reversely
transducing costimulating signals into T cells,
TNFRSF6B can also block such reverse signaling. The
end result is that TNFRSF6B can reduce several
costimulation pathways in T cells and inhibit T cell
immune responses, such as cytokine secretion and
proliferation in vitro, and cardiac allograft rejection in
vivo in mouse models.
When human TNFRSF6B is linked to a transmembrane
domain and is expressed on the mouse tumor cell
surface, it can effectively trigger T cell costimulation
via LIGHT and FasL reverse signaling, and cause
effective tumor vaccination in mouse models.
When human TNFRSF6B is transgenically expressed
in mice, it causes a systemic lupus erythrematosus-like
syndrome. The expression of TNFRSF6B in bone
Expression
Normal tissue and cells express low-level TNFRSF6B,
and healthy individuals have near-background serum
TNFRSF6B levels. About 60% of malignant tumors of
various tissue origins overexpress TNFRSF6B, and
these patients have elevated serum TNFRSF6B levels.
Serum TNFRSF6B levels of tumor patients are
positively correlated to the degree of tumor malignancy
and status of metastasis. It is hypothesized that
malignant tumor cells secrete TNFRSF6B as a way to
achieve survival advantage by blocking multiple
apoptosis pathways.
Hepatocytes in liver cirrhosis have augmented
TNFRSF6B expression and patients with liver cirrhosis
have increased serum TNFRSF6B levels.
TNFRSF6B expression is low in resting T cells but is
augmented in activated T cells, which probably
represents a fine-tuning mechanism to balance the need
for clonal expansion and subsequent massive
activation-induced T cell death. About 40% of systemic
lupus erythematosus patients have elevated serum
TNFRSF6B levels.
TNFRSF6B expression in rheumatoid arthritis
fibroblast-like synoviocytes is increased by TNFalpha.
Localisation
TNFRSF6B is a secreted protein, and is thus detected
in body fluids. However, it can also be detected in
cytoplasm before it is secreted.
Function
As TNFRSF6B can block ligands from interacting with
Fas, HVEM, LTbetaR, and DR3, all of which mediate
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4)
335
TNFRSF6B (tumor necrosis factor receptor superfamily, member 6b, decoy)
marrow-derived cells is sufficient to induce this
phenotype.
Recombinant human TNFRSF6B ameliorates an
autoimmune crescentic glomerulonephritis model in
mice.
TNFRSF6B can influence dendritic cells which in turn
drive T cells to differentiate into Th2 cells.
TNFRSF6B can inhibit actin polymerization of T cells
upon mitogen stimulation, and repress T-cell
pseudopodium formation, which is known to be
important for cell-cell interaction. As a consequence,
T-cell aggregation after activation is suppressed by
either soluble or solid phase TNFRSF6B.
Human T cells pretreated with soluble or solid-phase
TNFRSF6B are compromised in migration in vitro and
in vivo toward CXCL12. Mechanistically, a small
GTPase Cdc42 fails to be activated after TNFRSF6B
pretreatment of human T cells, and further downstream,
p38 mitogen-activated protein kinase activation, actin
polymerization, and pseudopodium formation are all
down-regulated in the treated T cells.
Phagocytic activity toward immune complexes and
apoptotic bodies as well as the production of free
radicals and proinflammatory cytokines in response to
lipopolysaccharide are impaired in TNFRSF6B-treated
macrophages.
augment during SLE flare-up. In animal models,
human TNFRSF6B overexpression in mouse cells of
hematopoietic origin leads to a SLE-like syndrome,
suggesting a pathogenic role of TNFRSF6B in SLE.
Diagnosis: Serum TNFRSF6B can be used as a
diagnostic parameter for SLE and SLE disease activity.
Therapeutics: Due to the pathogenic effect of
TNFRSF6B on SLE, it is speculated that neutralizing
TNFRSF6B might have therapeutic effect on a
subpopulation of SLE patients, who are serum
TNFSF6B positive.
Islet primary nonfunction during islet
transplantation
Disease
Therapeutics: Due to the anti-apoptotic effect of
TNFRSF6B, it can effectively protect islets from
apoptosis during their isolation, transportation, and
primary non-function after transplantation.
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This article should be referenced as such:
Ka SM, Sytwu HK, Chang DM, Hsieh SL, Tsai PY, Chen A.
Decoy receptor 3 ameliorates an autoimmune crescentic
glomerulonephritis model in mice. J Am Soc Nephrol
2007;18(9):2473-2485.
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