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(Received for publication, October 4, 1994; and in revised form, November 4, 1994) From the
Signaling by the p55 tumor necrosis factor (TNF) receptor and by
the structurally related receptor Fas/APO1 is initiated by receptor
clustering. Data presented here and in other recent studies (Wallach,
D., Boldin, M., Varfolomeev, E. E., Bigda, Y., Camonis, H. J. and Mett,
I.(1994) Cytokine 6, 556; Song, H. Y., Dunbar, J. D., and
Bonner, D. B.(1994) J. Biol. Chem. 269, 22492-22495)
indicate that part of that region within the intracellular domains of
the two receptors that is involved in signaling for cell death, as well
as for some other effects (the ``death domain'', specifically
self-associates. We demonstrate also the expected functional
consequence of this association; a mere increase in p55 TNF receptor
expression, or the expression just of its intracellular domain, is
shown to trigger signaling for cytotoxicity as well as for interleukin
8 gene induction, while expression of the intracellular domain of
Fas/APO1 potentiates the cytotoxicity of co-expressed p55 TNF receptor.
These findings indicate that the p55 TNF and Fas/APO1 receptors play
active roles in their own clustering and suggest the existence of
cellular mechanisms that restrict the self-association of these
receptors, thus preventing constitutive signaling. Many cell surface receptors are triggered upon clustering.
Unless restricted, this mode of triggering may result in their
spontaneous signaling due to receptor chance encounters. The
implications with regard to regulation of receptor function are
underscored by the findings in the present study regarding the
mechanisms of signaling by the p55 tumor necrosis factor (TNF) (
Self-association of the death domain in the p55-R was
observed by happenstance, on screening a HeLa cell cDNA library by the
two-hybrid system technique (14) for proteins that bind to the
intracellular domain of this receptor. Among the cDNAs whose products
bound specifically to the intracellular domain-GAL4 DBD fusion-protein,
several clones encoded parts of the p55-R intracellular domain (p55-IC;
marked with asterisks in Table 1).
The extent of specificity
in the self-association of p55-IC and the particular region involved
was evaluated by the two-hybrid test. Table 1shows the
following. (a) The self-association of p55-IC is confined to a
region within the death domain. Its N terminus is located between
residues 328 and 344; its C terminus, close to residue 404, is somewhat
upstream of the reported C terminus of this domain (residue 414). (b) Deletion of the membrane-proximal part of p55-IC upstream
of the death domain enhanced self-association, suggesting that this
region has an inhibitory effect. (c) Mouse p55-IC
self-associates and also associates with the death domain of human
p55-R. (d) Examination of the self-association of the
intracellular domains of three other receptors of the TNF/NGF receptor
family: Fas/APO1, CD40(22) , and the p75 TNF
receptor(23) , showed that Fas-IC, which signals for cell death
by a sequence motif related to the p55-R death domain, self-associates
and associates to some extent with the p55-IC. However, CD40-IC, which
provides growth stimulatory signals (even though also containing a
sequence resembling the death domain), and p75-IC, which bears no
structural resemblance to p55-IC, do not self-associate, nor do they
bind p55-IC or Fas-IC. An in vitro test of the interaction
of a p55-IC-GST bacterial fusion protein with a p55-IC-MBP fusion
protein confirmed that p55-R self-associates and ruled out involvement
of yeast proteins (Fig. 1). The association was not affected by
increased salt concentration or by EDTA (Fig. 1, lanes 3 and 4).
Figure 1:
Self-association of the intracellular
domain of p55-R in vitro: specific association of
bacterially-produced fusion proteins containing the intracellular
domain. Interaction between fusion of human p55-IC to MBP (MBP-p55-IC)
and to GST (lane 2) and the effect of EDTA (lane 3)
and increased salt concentration (0.4 M KCl, lane 4)
on this interaction. Interaction of MBP-p55-IC with GST (lane
1) and of GST-p55-IC with the fusion product of MBP and an
irrelevant peptide (residues 195-229 in the mouse p75 TNF-R,
MBP-p75-EC, lane 5; position indicated by an arrow)
were also tested. SDS-polyacrylamide gel electrophoresis (10%
acrylamide) of the interacting proteins, followed by Western blotting,
using anti-MBP antiserum, was performed as described under
``Experimental Procedures.''
To evaluate the functional implications of the
self-association of the death domain, we examined the way in which
induced expression of p55-R, or of parts of it, affects cells sensitive
to TNF cytotoxicity. Using an expression vector that permits strictly
controlled expression of transfected cDNAs by a tetracycline regulated
transactivator(17) , we found that merely increasing p55-R
expression in HeLa cells by expression of transiently transfected cDNA
for the full-length receptor resulted in quite extensive cell death.
Even greater cytotoxicity was observed when expressing just p55-IC ( Fig. 2and 3, A and B). Significant
cytotoxicity was also observed when expressing just the death domain.
In contrast, expression of parts of the p55-IC that lacked the death
domain or contained only part of it (or expression of the luciferase
gene, used as an irrelevant control) had no effect on cell viability.
Expression of Fas-IC did not result in cytotoxicity, yet significantly
enhanced the cytotoxicity of co-expressed p55-R (Fig. 2). The
cytotoxicity of p55-IC was further confirmed using cells stably
transfected with its cDNA; these cells continued to grow when p55-IC
expression was not induced but died when p55-IC was expressed (Fig. 3C).
Figure 2:
Ligand-independent triggering of a
cytocidal effect in HeLa cells transfected with p55-R, or parts
thereof, or with Fas-IC. TNF receptor expression (left and middle) and viability (right) in: A, HeLa
cells expressing transiently the full-length p55-R (p55-R), p55-IC or
parts thereof or, as a control, luciferase (LUC); and B, in cells expressing Fas-IC, alone or together with the
p55-R, using a tetracycline-controlled expression vector.
Figure 3:
Ligand-independent triggering of a
cytocidal effect in HeLa cells transfected with p55-R or its
intracellular domain: kinetic study of transient expression of the
receptor and its expression in a stable transfectant. A, TNF
receptor expression (assessed by ELISA); B, cell viability, in
transient transfection of the full-length receptor (
We examined also the effects of increased
expression of p55-R and expression of just the intracellular domain of
the receptor on the transcription of IL-8, known to be activated by
TNF(19) . As shown in Fig. 4, transfection of HeLa cells
with a tetracycline-controlled construct encoding the p55-R cDNA
induced IL-8 transcription. An even stronger induction was observed in
cells transfected with the cDNA for p55-IC. In both cases, the
induction occurred only when tetracycline was excluded from the cell
growth medium, indicating that it occurs as a consequence of expression
of the transfected p55-R or p55-IC. Transfection with luciferase cDNA,
as a control, had no effect on IL-8 transcription.
Figure 4:
Ligand-independent induction of IL-8 gene
expression in HeLa cells transfected with p55-R or its intracellular
domain. A, Northern analysis of RNA (7 µg/lane), extracted
from HeLa (HTta-1) cells, untreated or treated with TNF (500 units/ml
for 4 h; autoradiography performed for 6 h), or the HTta-1 cells 24 h
after their transfection (in the presence or absence of tetracycline)
with p55-IC, the p55-R or luciferase cDNA (autoradiography for 18 h). B, methylene blue staining of 18 S rRNA. For other details,
see ``Experimental Procedures.''
Studies employing the two-hybrid technique suggested that the
intracellular domain of the p55-R self-associates and located this
self-association to a part of a region found to be critical for
signaling by this receptor ( (4) and the present report; see
also (33) ). Further tests confirmed that this association is
not artifactual, as may well occur in the yeast genetic
test(24) , and indicated that it has functional consequences.
The self-association could be shown to occur also in vitro,
using GST and MBP p55-IC fusion proteins, thus ruling out involvement
of yeast proteins or of the Gal4 DBD or AD in this association.
Moreover, the expected functional consequence of this association could
be demonstrated, namely occurrence of spontaneous signaling under
conditions that permit receptor aggregation. A mere increase in p55-R
expression, or even expression just of the intracellular domain of the
receptor or of its death domain, was found to be sufficient to trigger
signaling for cytotoxicity as well for expression of the TNF-inducible
IL-8 gene within cells. Normally, cells expressing the p55-R do not
exhibit TNF effects unless exposed to this cytokine. Presumably, cells
possess some mechanisms that reduce the self-association of the
receptor and impose on it ligand dependence. Probably self-association
of the receptors is in part restricted by mechanisms that maintain
their self-surface expression at a low level. It may also be restricted
by constraints imposed on the death domain in the receptor by other
regions in the p55-R molecule. To some extent, self-association of the
death domain seems to be inhibited by the membrane-proximal part of the
intracellular domain (Table 1). Crystallographic studies of the
extracellular domain of the receptor suggest that also this domain
mediates an inhibitory effect; they indicate that, in the absence of
TNF, the extracellular domains of neighboring p55-R molecules are
capable of interacting in a way that obviates association of their
intracellular domains. ( The intracellular
domain of Fas/APO1, which bears marked structural similarity to that of
the p55-R and that likewise signals for cell death, was found also to
self-associate and thus trigger signaling, suggesting that this
receptor, too, plays an active role in its aggregation and is subject
to control mechanisms that antagonize its propensity to self-associate.
This may well be the case also for a number of other receptors, for
example several tyrosine-kinase receptors, including Neu/HER-2 and the
epidermal growth factor receptor, that are found, just like the p55-R,
to signal spontaneously when expressed at high levels as well as after
deletion of their extracellular domain (see, e.g., (25, 26, 27) , and references therein). Interestingly, the p75 TNF receptor, even though it has, like p55-R
and Fas/APO, the ability to signal for cell death(28) , does
not display self-association, nor does a high level of expression of
this receptor result in spontaneous signaling(29) . Apparently,
the mode of signaling for cell death by this receptor differs from that
of the p55-R(29) . Most likely, the self-associations of
p55-R and Fas/APO1 serve to fortify the aggregated state imposed on
them by their ligands. Such a mechanism has certain functional
advantages. It may augment signaling and also provide ways for
modulation of signaling by mechanisms that act within the cell. An
intriguing possibility for such modulation is indicated by the slight
association between p55-IC and Fas-IC, which may allow cross-talk
between the two cell death-inducing receptors(7) . The
propensity of these receptors to self-associate may permit also a kind
of derangement of regulation that would not be expected if their
aggregation occurred in a passive manner. It can lead to spontaneous
signaling, independent of the ligand, in situations in which the
mechanisms restricting the self-association of the receptors fail to
function properly. Such ligand-independent function is, in the case of
growth factor receptors, a well known cause for the uncontrolled growth
of malignant cells. In receptors that signal for cytotoxicity, it may
contribute to uncalled-for death of cells, as observed, for example, in
response to cytopathic viruses and various other pathogens.
Volume 270,
Number 1,
Issue of January 6, 1995 pp. 387-391
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Death Domains
of the p55 Tumor Necrosis Factor
(TNF) Receptor and Fas/APO1 Prompts Signaling for TNF and Fas/APO1
Effects (*)
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
)receptor (p55-R) and Fas/APO1. These two structurally
related receptors provide signals that can cause the death of cells
expressing them, via structurally related sequence motifs in their
intracellular domains (the ``death domains''; Refs. 2, 5, and
6). Dominant negative effects of mutations in these domains (2) and mimetic effects of antibodies against the two receptors (1, 7, 8) indicate that their signaling is
initiated as a consequence of their clustering and self-interaction.
TNF, and quite likely also the closely similar Fas ligand(9) ,
occur as homotrimeric molecules (see, e.g., (10) and (11) ) and thus can induce clustering of receptors merely by
binding to them. Data presented here (see also (33) ) and in
another recent study (4) show, however, that the intracellular
domains of p55-R and of Fas/APO1 can aggregate even in the absence of
their ligands, prompted by the ability of their death domains to
self-associate. Additionally, we show that an increase in expression of
these receptors, or even just of their death domain, can result in the
induction of TNF and Fas/APO1-like effects, suggesting that the
self-association of the death domain suffices to trigger signaling.
These findings emphasize the need to elucidate how spontaneous
signaling as a consequence of chance encounters between receptors
normally is prevented.
Two-hybrid Screen and Two-hybrid
cDNA inserts were cloned by polymerase chain
reaction, either from the full-length cDNAs cloned previously in our
laboratory, or from purchased cDNA libraries. 
-Galactosidase
Expression Test-Galactosidase
expression in yeasts (SFY526 reporter strain; (12) )
transformed with these cDNAs in the pGBT-9 and pGAD-GH vectors (DNA
binding domain (DBD) and activation domain (AD) constructs,
respectively) was assessed by a liquid test(13) , as well as by
a filter assay, which yielded qualitatively the same results (not
shown). Two-hybrid screening (14) of a Gal4 AD-tagged HeLa cell
cDNA library (Clontech, Palo Alto, CA) for proteins that bind to the
intracellular domain of the p55-R (p55-IC), was performed using the HF7c yeast reporter strain. Positivity of the isolated clones
was assessed by (a) prototrophy of the transformed yeasts for
histidine when grown in the presence of 5 mM 3-aminotriazole, (b) -galactosidase expression, and (c)
specificity tests (interaction with SNF4 and lamin fused to Gal4 DBD).In Vitro Self-association of Bacterially Produced p55-IC
Fusion Proteins
Glutathione S-transferase (GST) and
glutathione S-transferase-p55-IC fusion protein (GST-p55-IC)
were produced as described elsewhere(15, 16) .
Maltose-binding protein (MBP) fusion proteins were obtained using the
pMalcRI vector (New England Biolabs) and purified on an amylose resin
column. The interaction of the MBP and GST fusion proteins was
investigated by incubating glutathione-agarose beads sequentially with
the GST and MBP fusion proteins (5 µg of protein/20 µl of
beads), first for 15 min and then for 2 h, at 4 °C. Incubation with
MBP fusion proteins was carried out in a buffer solution containing 20
mM Tris-HCl, pH 7.5, 100 mM KCl, 2 mM CaCl
, 2 mM MgCl, 5 mM dithiothreitol, 0.2% Triton X-100, 0,5 mM phenylmethylsulfonyl fluoride, and 5% (v/v) glycerol or, when
indicated, in that same buffer containing 0.4 M KCl or 5
mM EDTA instead of MgCl. Association of the MBP
fusion proteins was assessed by SDS-polyacrylamide gel electrophoresis
of the proteins associated with the glutathione-agarose beads, followed
by Western blotting. The blots were probed with rabbit antiserum
against MBP (produced in our laboratory) and with
horseradish-peroxidase-linked goat anti-rabbit immunoglobulin.Induced Expression in HeLa Cells of the p55-R, Fragments
Thereof, and Fas-IC
HeLa cells expressing the
tetracycline-controlled transactivator (the HtTA-1 clone; (17) ) were grown in Dulbecco's modified Eagle's
medium, containing 10% fetal calf serum, 100 units/ml penicillin, 100
µg/ml streptomycin, and 0.5 mg/ml neomycin. cDNA inserts encoding
the p55-R or parts thereof were introduced into a
tetracycline-controlled expression vector (pUHD10-3, provided by
H. Bujard). The cells were transfected with the expression construct (5
µg of DNA/6-cm plate) by the calcium phosphate precipitation method (16) . Effects of transient expression of the transfected
proteins were assessed at the indicated times after transfection in the
presence or absence of tetracycline (1 µg/ml). Clones of cells
stably transfected with the human p55-IC cDNA in the pUHD10-3
vector were established by transfecting the cDNA to HtTA-1 cells in the
presence of tetracycline together with a plasmid conferring resistance
to hygromycin, followed by selection for clones resistant to hygromycin
(200 µg/ml). Expression of the cDNA was obtained by removal of
tetracycline, which was otherwise maintained constantly in the cell
growth medium.Assessment of TNF-like Effects Triggered by Induced
Expression of the p55-R, Fragments Thereof, or Fas-IC
Effects of
induced expression of the receptors and of TNF on cell viability were
assessed by the neutral-red uptake method(18) . Induction of
interleukin 8 (IL-8) gene expression was assessed by Northern analysis.
RNA was isolated using TRI Reagent (Molecular Research Center, Inc.),
denatured in formaldehyde/formamide buffer, electrophoresed through an
agarose/formaldehyde gel, and blotted to a GeneScreen Plus membrane
(DuPont) in 10 
SSPE buffer, using standard techniques. Filters
were hybridized with an IL-8 cDNA probe ((19), nucleotides
1-392), radiolabeled by random primed DNA labeling kit
(Boehringer, Mannheim, Germany), and washed stringently.Assessment of TNF Receptor Expression
TNF receptor
expression in samples of 1 10
cells was assessed by
measuring the binding of TNF, labeled with I by the
chloramine-T method, as described previously(20) . It was also
assessed by ELISA, performed as described for the quantification of the
soluble TNF receptors(21) , except for the use of radioimmune
precipitation buffer (10 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1% Nonidet P-40, 1% deoxycholate, 0.1% SDS, 1 mM EDTA, and 1 mM phenylmethylsulfonyl fluoride) to lyse the
cells (70 µl/10
cells) and to dilute the tested
samples. The soluble form of the p55-R, purified from urine, served as
the standard.
,
cells transfected in the presence of tetracycline (1 µg/ml), which
inhibits expression; , cells transfected in the absence of
tetracycline. TNF receptor expression was assessed 20 h after
transfection, both by ELISA, using antibodies against the
receptor's extracellular domain (left), and by
determining the binding of radiolabeled TNF to the cells (middle). The cytocidal effect of the transfected proteins was
assessed 48 h after transfection. Data shown are from one of three
experiments with qualitatively similar results, in which each construct
was tested in duplicate. ND, not
determined.
,
)
and of p55-IC (
, 
) in the presence or absence of
tetracycline (empty and solid notes, respectively), assessed at various
times after incubation with the transfected DNA; C, effect of
p55-IC expression on the viability of cells transfected stably with
this cDNA, assessed at various times after replacement of the cell
growth medium with fresh medium either with or without tetracycline.
Photographs were taken 36 h after tetracycline
removal.
)Such interaction may well prevent
spontaneous signaling by the receptors and allow their intracellular
domains to self-associate only after TNF binding.
))
We are grateful to Drs. Herman Bujard and Sabina
Freundlieb for providing us with the reagents for
tetracycline-controlled expression and to Ada Dibeman for careful
handling of the cultured cells.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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 C. A. Patel, M. Mukhtar, and R. J. Pomerantz Human Immunodeficiency Virus Type 1 Vpr Induces Apoptosis in Human Neuronal Cells J. Virol., October 15, 2000; 74(20): 9717 - 9726. [Abstract] [Full Text]
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S. Chatterjee, H. Han, S. Rollins, and T. Cleveland Molecular Cloning, Characterization, and Expression of a Novel Human Neutral Sphingomyelinase J. Biol. Chem., December 24, 1999; 274(52): 37407 - 37412. [Abstract] [Full Text] [PDF]
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S.-L. Chan, K.-O. Tan, L. Zhang, K. S. Y. Yee, F. Ronca, M.-Y. Chan, and V. C. Yu F1Aalpha , a Death Receptor-binding Protein Homologous to the Caenorhabditis elegans Sex-determining Protein, FEM-1, Is a Caspase Substrate That Mediates Apoptosis J. Biol. Chem., November 5, 1999; 274(45): 32461 - 32468. [Ab |
