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J Biol Chem, Vol. 273, Issue 45, 29648-29653, November 6, 1998
From the Caspases are a family of cysteine proteases
related to interleukin-1 converting enzyme (ICE) and represent the
effector arm of the cell death pathway. The zymogen form of all
caspases is composed of a prodomain plus large and small catalytic
subunits. Herein we report the characterization of a novel caspase,
MICE (for mini-ICE), also designated
caspase-14, that possesses an unusually short prodomain and is highly
expressed in embryonic tissues but absent from all adult tissues
examined. In contrast to the other short prodomain caspases (caspase-3,
caspase-6, and caspase-7), MICE preferentially associates with large
prodomain caspases, including caspase-1, caspase-2, caspase-4,
caspase-8, and caspase-10. Also unlike the other short prodomain
caspases, MICE was not processed by multiple death stimuli including
activation of members of the tumor necrosis factor receptor family and
expression of proapoptotic members of the bcl-2 family. Surprisingly,
however, overexpression of MICE itself induced apoptosis in MCF7 human breast cancer cells, which was attenuated by traditional caspase inhibitors.
Major advances have been made toward understanding the molecular
mechanism of programmed cell death (1). Functioning as central
components of the cell death signaling pathway are a rapidly growing
family of cysteine proteases that cleave following aspartate residues
(caspases)1 (2, 3). Caspases
are normally present as single polypeptide zymogens and contain an
N-terminal prodomain and large (p20) and small (p10) catalytic subunits
(4-6). The 2-chain active enzyme is obtained following proteolytic
processing at internal Asp residues (4-6). As such, caspases are
capable of activating each other in a manner analogous to the
processing of zymogens observed in the coagulation cascade.
To date, twelve caspases have been identified that can be classified
into three subfamilies: caspase-1 (interleukin-1 converting enzyme),
caspase-4 (ICErelII, TX, ICH2), caspase-5 (ICErelIII, TY), caspase-11
(Ich-3), and caspase-12 belong to the caspase-1 subfamily; caspase-2
(Ich-1) is the sole member of the caspase-2 subfamily; caspase-8
(FLICE, MACH, Mch5), caspase-9 (ICE-LAP6, Mch6), caspase-10 (FLICE2,
Mch4), caspase-3 (Yama, CPP32, apopain), caspase-7 (ICE-LAP3, Mch3,
CMH-1), and caspase-6 (Mch2) belong to the caspase-3 subfamily (2, 3,
7). An alternate classification is based on the size of the prodomain
because large prodomain caspases function as upstream signal
transducers, whereas short prodomain caspases function as downstream
amplifiers that cleave death substrates (8). It is not entirely clear
how large prodomain caspases are activated; however, recent studies
suggest that their binding to receptor-associated adaptor molecules
results in their approximation and activation by autoprocessing
(8-12).
Three short prodomain caspases exist in the caspase-3 subfamily,
whereas none have been found in the other two subfamilies (2, 3). Here
we report a novel developmentally regulated short prodomain caspase
designated MICE or caspase-14 that is a member of the caspase-1
subfamily and possesses unique biochemical properties.
Cell Lines and Expression Vectors--
Human embryonic kidney
293 and 293-EBNA cells were cultured in Dulbecco's modified Eagle's
medium containing 10% fetal bovine serum, nonessential amino acids,
L-glutamine, and penicillin/streptomycin. Human breast
carcinoma MCF7 cells were maintained in RPMI 1640 containing 10%
heat-inactivated fetal bovine serum, nonessential amino acids,
L-glutamine, and penicillin/streptomycin. Expression constructs of tumor necrosis factor receptor family members were in
pFLAG-CMV-1 (Kodak). Bax, Bak, and Bik expression constructs were
generously provided by G. Chinnadurai, IAP1 and IAP2 by D. V. Goeddel, and Hrk by G. Nunez. All other expression constructs were made
in pcDNA3 (Invitrogen). Epitope tags were placed at the C termini
unless otherwise indicated.
Cloning of Caspase-14 (MICE)--
cDNA sequences
corresponding to the partial open reading frame of caspase-14 were
identified as expressed sequence tags (EST) (GenBankTM
accession numbers AA103647 and AA167930) homologous to caspase family
members. Both clones were sequenced using plasmid DNA template by the
dideoxy chain termination method employing modified T7 DNA polymerase
(Sequenase, United States Biochemical). The AUI epitope-tagged version
of MICE was obtained by polymerase chain reaction using custom
synthesized primers.
Northern Blotting--
Mouse adult multiple tissue and embryo
tissue poly (A)+ RNA blots were obtained from
CLONTECH and processed according to manufacturer instructions. A 32P-labeled cDNA corresponding to MICE
amino acid residues 44-152 was used as probe.
Transfection, Coimmunoprecipitation, and Western
Analysis--
Transient transfections of 293 cells were performed as
described previously (13). Cells were harvested 20-30 h following transfection and either immunoprecipitated and immunoblotted or directly immunoblotted with the indicated antibodies.
Cell Death Assay--
293 EBNA cells and MCF7 cells were
transiently transfected with 0.1 and 0.25 µg of the reporter plasmid
pCMV Mice Expression and Purification--
Recombinant MICE was
expressed in Escherichia coli strain Bl21 (DE3) plysS
following induction for 4 h at 37 °C with 0.2 mM isopropyl-1-thio- Mice Activity Assay--
Purified MICE (10 µl) was added to 40 µl of caspase assay buffer (20 mM PIPES, 100 mM NaCl, 10 mM dithiothreitol, 1 mM
EDTA, 0.1% CHAPS, 10% sucrose, pH 7.2) in the absence (control) or
presence of the following caspase inhibitors: 2 µM
Z-VAD-FMK, or 5 µM CrmA(REF) or 0.3 µM p35,
followed by incubation at 37 °C for 30 min to allow for complex
formation. Residual activity was assayed by adding 50 µl of a 0.2 mM solution of the caspase substrate Ac-DEVD-AFC, and
measurement of released AFC at 37 °C using a Perkin-Elmer LS50
spectrofluorimeter with excitation at 400 nm and emission at 505 nm.
MICE Is a Short Prodomain Caspase of Caspase-1
Subfamily--
Analysis of the full-length cDNA sequence of MICE
revealed a 774-base pair open reading frame that encoded a novel
protein of 257 amino acids with a predicted molecular mass of 29.5 kDa (Fig. 1A). Comparison of this
protein with all known caspases revealed that it had a unusually short
prodomain of only six amino acids (Fig. 1, A and
C). Given this, the molecule was termed MICE (for mini-ICE).
The caspase designation for it is caspase-14.
Phylogenetic analysis revealed MICE to be most related to caspase-1
subfamily members, and it is therefore the first short prodomain
caspase to be part of the caspase-1 subfamily (Fig. 1B).
Overall, MICE displayed 21.4, 19.5, and 20.2% identity to the known
short prodomain caspases 3, 6, and 7, respectively (Fig. 1C). The QACRG pentapeptide motif present in most caspases
is also conserved in this novel caspase. In addition, based on the x-ray crystal structure of caspase-1 and caspase-3, amino acid residues
involved in catalysis are conserved in MICE as are residues that form a
binding pocket for the carboxylate side chain of the P1 aspartic acid
(Fig. 1C) (4-6). This is in keeping with MICE being a
functional caspase.
Tissue Distribution of MICE--
Mouse adult and embryonic tissue
poly(A)+ RNA blots were probed with a
32P-labeled cDNA corresponding to the large catalytic
subunit of MICE. A single transcript of 2.8 kilobases was observed
(Fig. 2). Unlike almost all known
caspases that are expressed in both adult and embryonic tissues (7, 10,
11, 14-18), MICE was highly expressed in certain stages of embryonic
development but was undetectable in all adult tissues examined,
including heart, brain, spleen, lung, liver, skeletal muscle, kidney,
and testis. Interestingly, the expression level of MICE appeared to
increase during the later stages of development (the attenuated
expression in day 11 may be because of lower loading of mRNA).
MICE Preferentially Associates with Certain Large Prodomain
Caspases--
Because small prodomain caspases function downstream of
large prodomain caspases, we asked if MICE, being a short prodomain caspase, bound any of the putative upstream large prodomain caspases. Surprisingly, MICE associated with most large prodomain caspases, including caspase-1, -2, -4, -8, and -10 (Fig.
3A). The other short prodomain
caspases including caspase-3, -6, and -7 associated only with
caspase-10 (data not shown). MICE did not bind the other short
prodomain caspases and displayed only weak self-association in contrast
to caspase-3 and other caspases that strongly self-associated (Fig.
3B, and unpublished data). The preferential dimerization with large prodomain caspases and weak self-association suggest that
MICE may function through heterodimerization.
MICE Is Not Processed in Multiple Death Signaling
Pathways--
Previous studies have shown that initially long
pro-domain and then short pro-domain caspases are processed following
activation of death receptors including TNFR1 and CD95 death receptors
(19-24). To further characterize MICE, we asked if it was processed on activation of these receptors. 293 cells were transiently transfected with expression constructs encoding death signaling receptors and MICE,
or the three known short prodomain caspases: caspase-3, -7, and -6. Interestingly, all three known short prodomain caspases were processed
upon coexpression with the death signaling receptors (Fig.
4A). MICE, however, was not
processed, suggesting that it is not involved in the death pathway
engaged by these proapoptotic receptors (Fig. 4A).
Bax, Bak, Bik, Bad, Bid, and Hrk are proapoptotic members of the bcl-2
family (23, 25). 293 cells were transiently transfected with expression
constructs encoding short prodomain caspases and proapoptotic bcl-2
family members. In keeping with the prior results, all three known
short prodomain caspases were processed on co-expression, but MICE was
not processed (Fig. 4B).
Because MICE was not processed on activation of a number of distinct
physiologically relevant death pathways, we asked if it could serve as
a substrate for known caspases. Expression constructs encoding MICE and
known caspases were coexpressed in the presence or absence of the death
signaling receptor TNFR1. Consistent with previous results, no
processing of MICE was observed despite the additional death signal
from TNFR1 (Fig. 4C). MICE was also not processed by
caspase-1 or -4, both members of the caspase-1 subfamily (data not
shown). The failure of processing of MICE suggests that it likely
functions in a very specific pathway that remains to be defined.
MICE-induced Apoptosis Is Attenuated by Inhibitors of
Apoptosis--
To determine whether MICE plays a role in cell death,
293 EBNA and MCF7 cells were transfected with expression plasmids
encoding wild-type MICE, a mutant version of MICE in which the presumed catalytic cysteine was altered to an alanine (QACRG to QAARG mutant) and caspase-8 as a positive control that has previously been shown to
potently induce apoptosis in both cell lines (9, 10). Like the three
other known short prodomain caspases, MICE had little effect on 293 EBNA cells (Fig. 5A, and
unpublished data). However, it induced apoptosis in MCF7 cells (Fig.
5A). As expected, catalytically inactive MICE displayed
substantially less death-inducing activity. More importantly,
MICE-induced apoptosis in MCF7 was inhibited by the baculoviral-encoded
inhibitors of apoptosis 1 and 2 (IAP1 and IAP2) and the broad spectrum
baculoviral caspase inhibitor p35, but not by CrmA, MC159, or I-FLICE
(Fig. 5B). CrmA is a cowpox serpin that inhibits caspase-1
and -8 activity, whereas MC159 is a death effector domain-containing
decoy molecule encoded by molluscum contagiosum virus (26-27). I-FLICE
is a naturally occurring catalytically inert dominant-negative caspase
(28). These inhibitors function at the apex of the apoptotic cascade by
disrupting assembly of receptor signaling complexes and/or inhibiting
the initiating caspase (27-29). Because they had no effect on cell
death induced by MICE, it is possible that MICE functions as a
downstream signal transducer of cell death. However, it should be
emphasized that the results from these overexpression studies should
not be construed to imply a definitive role for caspase-14 in
apoptosis. This will have to await more definitive studies including
the generation of a mouse that is homozygous null for the gene in
question.
MICE Possesses Caspase Activity--
Recombinant MICE prepared
by overexpression in E. coli possessed intrinsic caspase
activity that was inhibitable by the broad spectrum caspase inhibitors
zVADfmk and p35 but not by CrmA (Fig. 6).
In summary, the failure of MICE to undergo processing in multiple known
death pathways and its ability to physically interact with large
prodomain caspases and induce cell death suggests that MICE likely
functions as a downstream active caspase in an as yet unidentified
signaling pathway.
We thank Yong Li for technical assistance and
Yongping Kuang and Ian Jones for help in preparing the figures.
*
This work was supported by National Institutes of Health
Grants ES08111 and AG13671.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The abbreviations used are:
caspase, cysteine
aspartate specific protease; ICE, interleukine-1 converting enzyme; MICE, mini-ICE; I-FLICE, inhibitor of Fas-associated death domain
protein (FADD)-like ICE; TNFR1, tumor necrosis factor receptor 1; IAP, inhibitor of apoptosis; PIPES, 1,4-piperazinediethanesulfonic acid; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid.
Caspase-14 Is a Novel Developmentally Regulated Protease*
,,¶
Department of Pathology, University of
Michigan Medical School, Ann Arbor, Michigan 48109, the
¶ Department of Molecular Oncology, Genentech, Inc., South San
Francisco, California 94080, and the § Burnham
Institute, La Jolla, California 92037
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
-galactosidase, respectively, plus 0.5-1.0 µg of test
plasmids in the presence or absence of 2.0 µg of inhibitory plasmids.
24-30 h following transfection, cells were fixed with 0.5%
glutaraldehyde and stained with 5-bromo-4-chloro-3-indolyl
-D-galactoside. Percentage of apoptotic cells was
determined by calculating the fraction of membrane-blebbed blue cells
as a function of total blue cells. All assays were evaluated in
duplicate, and the mean and standard deviation was calculated.
-D-galactopyranoside. Cells were
harvested by centrifugation, resuspended in 100 mM
Tris-HCl, 100 mM NaCl, pH 8, and lysed by freeze-thaw
cycles followed by sonication. The supernatant was recovered by
centrifugation and applied directly to immobilized Ni-nitrilotriacetic
acid for purification utilizing the engineered N-terminal His tag. The
protein was eluted with a 0-200 mM imidazole gradient, and
the recovered MICE was contaminated with an equal amount of E. coli histidine-rich protein. Final purification of MICE was
achieved by ion exchange utilizing a gradient of 0-500 mM
NaCl in 20 mM Tris-HCl following adsorption to
DEAE-Sepharose. Approximately 1 mg of MICE was obtained from 3 liters
of E. coli, and the final concentration was 0.3 mg/ml.
RESULTS AND DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
View larger version (79K):
[in a new window]
Fig. 1.
Sequence analysis of MICE. A,
deduced amino acid sequence of MICE. The conserved pentapeptide QACRG
is boxed, and the putative cleavage site between prodomain
and p20 and that between p20 and p10 are underlined.
B, phylogenetic analysis of caspase family. C,
sequence alignment of MICE and three known short prodomain caspases.
Solid circles indicate residues involved in catalysis, and
triangles identify residues that form the binding pocket for
the carboxylate side chain of P1 Asp. The putative cleavage sites
between prodomain and p20 are underlined. CASP-,
caspase.
View larger version (73K):
[in a new window]
Fig. 2.
Tissue distribution of MICE. Murine
adult multiple and embryo tissue poly(A)+ Northern blots
were probed with 32P-labeled MICE cDNA.
View larger version (44K):
[in a new window]
Fig. 3.
MICE preferentially associates with some
large prodomain caspases. 293 cells were co-transfected with the
expression constructs encoding epitope-tagged MICE and other caspases.
30 h following transfection, cells were harvested, lysed, and
analyzed with the indicated antibodies. The expression of each plasmid
was confirmed by either reprobing the blots or directly blotting the
cell lysate. mut, mutant; CASP-, caspase.
View larger version (55K):
[in a new window]
Fig. 4.
MICE is not processed on activation of known
death signaling pathways. 293 cells were co-transfected with
expression constructs encoding TNFR family members and either
C-terminal-tagged caspase-3-AU1, caspase-6-FLAG, caspase-7-FLAG, or
MICE-AU1 (A). MICE was also co-expressed with the
proapoptotic members of bcl-2 family (B) or caspases in the
absence or presence of TNFR1 (C). 20-24 h following
transfection, cells were harvested and either immunoprecipitated
(IP) and immunoblotted or directly immunoblotted with the
indicated antibodies. WB, Western blot; CASP-,
caspase; IP, immunoprecipitated.
View larger version (38K):
[in a new window]
Fig. 5.
MICE-induced apoptosis is attenuated by the
inhibitors of apoptosis. A, 293 and MCF7 cells were
co-transfected with a reporter gene ( -galactosidase) and expression
constructs encoding caspase-8 (CASP-8), MICE, and a mutant
version of MICE (mutMICE). B, MCF7 cells were
co-transfected with the reporter gene and MICE expression construct in
the absence or presence of the inhibitor plasmids. The cells were fixed
and stained as described under "Materials and Methods." Expression
of all transfected plasmids was verified by immunoblotting.
View larger version (22K):
[in a new window]
Fig. 6.
Characterization of MICE caspase
activity. The ability of recombinant MICE to cleave the
fluorometric caspase substrate Ac-DEVD-AFc is shown as a function of
the inhibitor present at time of initiation of assay.
ACKNOWLEDGEMENTS
FOOTNOTES
To whom correspondence should be addressed: Dept. of Molecular
Oncology, Genentech, Inc., 1 DNA Way, Bldg. 10, Rm. 290, South San
Francisco, CA 94080. Tel.: 650-225-1312; Fax: 650-225-6127; E-mail:
dixit{at}gene.com.
REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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