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    • Abstract: Published OnlineFirst September 29, 2009; DOI:10.1158/0008-5472.CAN-09-2148Phosphorylation-Dependent Lys63-LinkedPolyubiquitination of Daxx Is Essential for Sustained TNF- α−Induced ASK1 ActivationYayoi Fukuyo, Tetsuya Kitamura, Masahiro Inoue, et al.

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Published OnlineFirst September 29, 2009; DOI:10.1158/0008-5472.CAN-09-2148
Phosphorylation-Dependent Lys63-Linked
Polyubiquitination of Daxx Is Essential for Sustained TNF- α
−Induced ASK1 Activation
Yayoi Fukuyo, Tetsuya Kitamura, Masahiro Inoue, et al.
Cancer Res 2009;69:7512-7517. Published OnlineFirst September 29, 2009.
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Priority Report
Phosphorylation-Dependent Lys63-Linked Polyubiquitination
of Daxx Is Essential for Sustained TNF-A–Induced
ASK1 Activation
1 1,2 3 1 1
Yayoi Fukuyo, Tetsuya Kitamura, Masahiro Inoue, Nobuko T. Horikoshi, Ryuji Higashikubo,
1 4 1
Clayton R. Hunt, Anny Usheva, and Nobuo Horikoshi
1
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri; 2Department of Oral Pathology,
Hokkaido University, Sapporo, Japan; 3Department of Parasitology, Kurume University Medical School, Kurume, Japan; and
4
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
Abstract circuit is part of the mechanism by which p53 gain-of-function
Apoptosis signal–regulating kinase 1 (ASK1) is a key regulatory mutations contribute to tumorigenesis.
kinase in the proapoptotic response to various stresses. ASK1 Protein phosphorylation can induce polyubiquitination that
phosphorylation of Daxx, an ASK1 activator protein, increases results in proteasome-dependent protein degradation, a mecha-
Daxx accumulation in cells and further enhances ASK1 activity nism well documented for transcription factor NF-nB activation.
through a positive feedback mechanism. Here, we show that When TNF-associated factor 2 is activated, the NF-nB inhibitor InB
ASK1-dependent phosphorylation of Daxx induces Lys63 (K63)- is phosphorylated by IKKa/h kinase and subsequently undergoes
polyubiquitination-mediated degradation to release active NF-nB,
linked polyubiquitination on Lys122 of Daxx. Polyubiquitination
which then localizes to the nucleus (6). Target proteins destined for
is dispensable for Daxx accumulation or Daxx interaction with
degradation through 26S proteasome-dependent mechanisms are
ASK1 because mutant Daxx deficient in polyubiquitin still
generally conjugated with an identifying polyubiquitin chain(s)
exhibits ASK1-dependent accumulation and interaction with
linked through internal ubiquitin Lys48 (K48) residues (7). However,
cellular ASK1. However, K63-linked Daxx polyubiquitination is
required for tumor necrosis factor-A (TNF-A)–induced activa- recent studies have identified chain elongations that occur via
tion of ASK1. Therefore, K63-linked polyubiquitination of alternative ubiquitin lysine residues and that have proteasome-
Daxx functions as a molecular switch to initiate and amplify independent functions. One such example is Lys63 (K63)-mediated
the stress kinase response in the TNF-A signaling pathway. polyubiquitination, which can mediate cellular signaling, DNA
[Cancer Res 2009;69(19):7512–7] repair, protein localization, and endocytosis (8–10). The ubiquitin
ligases TNF-associated factors 2 and 6, which harbor intact RING
finger domains, mediate K63-linked polyubiquitination of them-
Introduction selves as well as stress-responsive kinases in signaling pathways
Apoptosis signal–regulating kinase 1 (ASK1) is a mitogen- activating JNK, p38, and IKK (11). Therefore, it is likely that the
activated protein kinase kinase kinase that plays an essential mode of ubiquitin chain linkage is closely related to their biological
role in the apoptotic response induced by tumor necrosis functions.
factor-a (TNF-a), Fas ligand, and oxidative stress (1, 2). We report here that, following Daxx phosphorylation by ASK1,
Activated ASK1 phosphorylates MKK4/MKK6 mitogen-activated Daxx undergoes K63-linked polyubiquitination that, although not
protein kinase kinases, leading to c-Jun NH2-terminal kinase required for either Daxx interaction with ASK1 or Daxx stabiliza-
(JNK)/p38 mitogen-activated protein kinase activation. ASK1 tion, plays a critical role in Daxx-mediated ASK1 activation.
can also be activated through direct interaction with Daxx, a
Fas death domain–binding protein (3). Moreover, a positive
feedback mechanism links Daxx and ASK1 (4), as ASK1 Materials and Methods
phosphorylation of two Daxx serine residues (Ser 176 and Plasmids construction. Specific Daxx substitution mutants were
Ser184) results in Daxx stabilization and accumulation, further generated by site-directed mutagenesis. Daxx 75K, 122K, 135K, 140-2K,
enhancing ASK1 activation. In contrast, tumorigenic mutant p53 208K, K0, and K122R were constructed by PCR with the primers:
directly interacts with Daxx and inhibits Daxx accumulation and
ASK1 activation, which prevents JNK activation and apoptosis K75R/F (5¶-CTTGAACTTTGTAGGATGCAGACAGCAGAC-3¶) and
(4, 5). These findings suggest that the Daxx-ASK1 positive K75R/R (5¶-GTCTGCTGTCTGCATCCTACAAAGTTCAAG-3¶),
feedback loop reinforces the amplification of downstream kinase K122R/F (5¶-CGGAGCCGGCCAGCGCGACTCTATGTCTAC-3¶) and
activations, including JNK and p38, and that breaking this K122R/R (5¶-GTAGACATAGAGTCGCGCTGGCCGGCTCCG-3¶),
K135R/F (5¶-CTCTGCACTGTTCTCAGGGCCCACTCAGCC-3¶) and
K135R/R (5¶-GGCTGAGTGGGCCCTGAGAACAGTGCAGAG-3¶),
Note: Supplementary data for this article are available at Cancer Research Online K140-2R/F (5¶-GCCCACTCAGCCAGACGTCGACTGAACTTGGCC-3¶)
(http://cancerres.aacrjournals.org/). and
Current address for Y. Fukuyo and N. Horikoshi: Department of Medicine, Beth K140-2R/R (5¶-GGCCAAGTTCAGTCGACGTCTGGCTGAGTGGGC-3¶),
Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
Requests for reprints: Nobuo Horikoshi, Department of Medicine, Beth Israel and
Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-728, K208R/F (5¶-CGGCGGCTGCAGGAACGCGAGTTGGATCTC-3¶) and
Boston, MA 02215. Phone: 617-735-3308; Fax: 617-735-3327; E-Mail: nhorikos@ K208R/R (5¶-GAGATCCAACTCGCGTTCCTGCAGCCGCCG-3¶).
bidmc.harvard.edu.
I2009 American Association for Cancer Research.
doi:10.1158/0008-5472.CAN-09-2148 Ub lysine mutants were constructed based on pCMV-Myc-His-Ub wild-type.
Cancer Res 2009; 69: (19). October 1, 2009 7512 www.aacrjournals.org
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Published OnlineFirst September 29, 2009; DOI:10.1158/0008-5472.CAN-09-2148
K63-Linked Polyubiquitination on Daxx Activates ASK1
Cell culture and transfection. Cells were cultivated in DMEM accumulation (Fig. 1A). Stabilization was also observed with
(HyClone) supplemented with 10% FCS. For transfection with plasmid a truncated enhanced green fluorescent protein (EGFP)-Daxx
DNA, 293 cells were transfected by using FuGene 6 (Roche) as (70-216), indicating that the domain(s) required for ASK1-depen-
recommended by the manufacturer. Transfections into either HeLa or dent stabilization should be localized within Daxx amino acids 70 to
MCF cells were done by electroporation with Nucleofector (Amaxa
216, which also contain the ASK1 phosphorylation sites Ser176 and
Biosystems) and OMNI kit (Magus Reagents) according to the manufac-
turer’s directions. For ubiquitination assays, 2 days after transfection, cells Ser184 (4). A similar Daxx accumulation was also observed in
were treated with 10 Amol/L proteasome inhibitor MG115 for 12 h and TNF-a–treated cells without ASK1 transfection (Fig. 1A).
harvested for protein analyses. For TNF-a stimulation, either HeLa or MCF7 It has been well documented that phosphorylation of InB, cyclin-
cells were treated with TNF-a (Peprotech) for 18 h. dependent kinase, or CDC25A triggers polyubiquitination of the
Immunoprecipitation and immunoblot analysis. Procedures for proteins (12, 13). Because Daxx undergoes proteasome-mediated
preparation of cell lysates, immunoprecipitation, and immunoblot are degradation (14, 15), we asked whether ASK1-dependent Daxx
described previously (5). The primary antibodies were anti–green phosphorylation affected its ubiquitination status. Immunoprecip-
fluorescent protein (B-2; Santa Cruz Biotechnology), anti-FLAG (M5; itation experiments revealed that active, but not kinase-defective,
Sigma), anti-HA (3F10; Roche), anti-Daxx (Sigma), anti-tubulin (Islet Cell ASK1 induced Daxx polyubiquitination of both ectopically
Antibody), and anti–poly(ADP-ribose) polymerase (Affinity Bioreagents).
expressed Daxx (Fig. 1B) and endogenous Daxx (Fig. 1C). As
expected from the previous results, the truncated form of FLAG-
Results and Discussion Daxx (amino acids 1-216) also showed ASK1-dependent polyubi-
ASK1 kinase stabilizes Daxx and induces Daxx ubiquitina- quitination as well (Supplementary Fig. S1).
tion. Gene transfection studies indicate that expression of wild- Phosphorylation of Daxx by ASK1 induces K63-linked
type, but not kinase-defective (K709M), ASK1 induces Daxx polyubiquitination on Daxx Lys122. ASK1-dependent Daxx
Figure 1. ASK1 stress kinase expression induces Daxx
polyubiquitination. A, ASK1 and TNF-a stabilize Daxx.
EGFP-Daxx or EGFP-Daxx (70-216) was expressed
in 293 cells in the presence of ASK1-HA wild-type (WT ) or
a kinase-dead (KD ; K709M) mutant or 18 h TNF-a
treatment. EGFP served as an expression control.
B, ASK1 increases polyubiquitination of Daxx. 293 cells
were transfected with expression plasmids for ASK1-HA
wild-type or kinase-defective together with FLAG-Daxx
and Myc-Ub and cultured for 48 h. Left, Daxx was
immunoprecipitated with anti-FLAG antibody and
the precipitated materials were analyzed by
immunoblotting with an antibody against Myc or FLAG.
IP, immunoprecipitation; IB, immunoblotting.
Right, reciprocal detection of ubiquitinated Daxx.
Ubiquitinated Daxx products are indicated as Daxx-Ub.
C, ASK1 induces the polyubiquitination of endogenous
Daxx. 293 cells expressing Myc-Ub together with ASK1-HA
wild-type or kinase-defective mutant were subjected to
immunoprecipitation with anti-Daxx antibody followed by
immunoblotting with anti-Myc or anti-Daxx antibodies.
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Figure 2. ASK1 induces K63-linked polyubiquitination of Daxx at K122. A, schematic diagrams of wild-type and mutant ubiquitin where arginine (R) amino acids
are substituted for lysine (K ). B, ASK1 induces K63-linked ubiquitination on endogenous Daxx. Cells were transfected with the indicated plasmids and cultured for 48 h.
Daxx was immunoprecipitated with anti-Daxx antibody and the precipitated materials were subjected to immunoblotting. C, schematic diagram of wild-type and
lysine mutants of Daxx. D, FLAG-Daxx mutants (K122R and 122K) were expressed in 293 cells together with ASK1-HA wild-type and Myc-Ub (48K or 63K).
phosphorylation followed by Daxx ubiquitination does not cause constructed (Fig. 2C). Among mutants, only the 122K revertant
Daxx degradation. Instead, phosphorylation results in Daxx Daxx mutant showed preferential K63-linked polyubiquitination
accumulation. The ubiquitin molecule contains seven lysines, over K48-linked polyubiquitination when expressed with ASK1
which are potential conjugation residues for ubiquitin polymeri- (Fig. 2D). Analysis using truncated Daxx (1-216) yielded similar
zation (ref. 16; Fig. 2A). To determine the mode of ASK1-induced results (Supplementary Fig. S3). Furthermore, the K122R mutant,
ubiquitin conjugation on Daxx, we tested ubiquitin mutants with a which is deficient in ubiquitination on Lys122 of Daxx, subsequently
single arginine-substituted mutation at position 63 (63R) or 48 showed a preferential K48-linked ubiquitin conjugation (Fig. 2D;
(48R) as well as mutants containing only one lysine at position 63 Supplementary Fig. S3). Immunoprecipitation experiments revealed
(63K) or 48 (48K) for their incorporation in polyubiquitin that all constructed Daxx mutants, including K0 and K122R, showed
chain(s) (Supplementary Fig. S2). The polyubiquitination of similar level of ASK1-Daxx interaction (Fig. 2D; Supplementary
endogenous Daxx was induced by active ASK1 with primarily Fig. S3). Therefore, K63-linked polyubiquitination of Lys122 in the
K63-linked but not K48-linked form (Fig. 2B). With kinase- Daxx molecule is not required for interaction with ASK1.
defective ASK1, significantly less K63-conjugated Daxx was The Lys122 ubiquitination site and surrounding amino acid
detected, confirming the requirement for ASK1 phosphorylation sequence is evolutionally well conserved as are the ASK1 target
of Daxx for K63-linked ubiquitination. To identify the primary serines, Ser176 and Ser184. This suggests that ASK1-dependent K63-
Daxx K63-linked ubiquitination site, a series of Daxx mutants linked polyubiquitination on Lys122 of Daxx could be an important
with lysine point mutations in the NH2-terminal region were regulatory mechanism for Daxx function throughout many species.
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K63-Linked Polyubiquitination on Daxx Activates ASK1
ASK1-dependent specific Daxx phosphorylation is required activation was strongly inhibited (Fig. 4B). In addition, TNF-a–
for K63-linked ubiquitination of Daxx. Because ASK1 kinase dependent apoptosis, as measured by poly(ADP-ribose) polymerase
activity is required for the K63-linked ubiquitination of Daxx, cleavage, was also prevented when the K122R mutant was
phosphorylation on Ser176 and Ser184 of Daxx is likely to play a expressed (Fig. 4C). The antiapoptotic effect of K122R mutant
critical role for its ubiquitination. The K63-linked ubiquitination of Daxx on TNF-a–dependent apoptosis was also shown by the
Daxx was induced by ASK1 transfection, whereas the phosphor- additional method of measuring sub-G1 fraction by fluorescence-
ylation-deficient mutant Daxx S176/184A had drastically reduced activated cell sorting analysis (Supplementary Fig. S4). In Daxx
K63-linked ubiquitination levels in ASK1-transfected cells (Fig. 3A). wild-type transfected cells, the sub-G1 fraction increased from
Kinase-defective ASK1 failed to induce ubiquitination of Daxx. 27.8% to 40.2% following TNF-a treatment, whereas transfection
Thus, the K63-linked ubiquitination of Daxx depends on phos- with the K122R mutant Daxx had essentially no effect on TNF-a–
phorylation of Daxx on Ser176 and Ser184 by ASK1. induced apoptosis (from 24.2% to 23.1% by TNF-a treatment).
Next, we analyzed whether phosphorylated Daxx was simulta- These results indicate that K63-linked polyubiquitination of
neously conjugated with K63 ubiquitin (Fig. 3B). Phosphorylated Daxx on K122 is essential for TNF-a–dependent ASK1 activation,
Daxx was immunoprecipitated with anti-phosphorylated Daxx– although K122 is dispensable for ASK1-induced Daxx accumula-
specific antibody (4), which recognizes phosphorylated Daxx tion. Because the K122 mutant Daxx still binds to ASK1 (Fig. 2D),
Ser176 and Ser184; then, the ubiquitination status of the immuno- K63-linked Daxx polyubiquitination is more likely involved in a
precipitated Daxx was analyzed. Phosphorylated FLAG-Daxx post-interaction ASK1 activation step. This is also supported by the
was preferentially conjugated with K63-linked polyubiquitination observation that the K122R Daxx mutant inhibited TNF-a–induced
rather than K48-linked polyubiquitination (Fig. 3B). These results JNK activation and apoptosis, thereby functioning as dominant-
show that ASK1-phosphorylated Daxx is preferentially K63-linked negative fashion (Fig. 4B and C).
polyubiquitinated. The NH2-terminal domain of ASK1 inhibits the endogenous
K63-linked polyubiquitination of Daxx is required for kinase activity (17), suggesting that the Daxx K63-linked poly-
TNF-A–induced sustained JNK activation and apoptosis. We ubiquitin tail may induce an ASK1 conformational change resulting
next determined the role of K63-linked Daxx ubiquitination in in kinase activation. Moreover, this NH2-terminal domain is also
TNF-a signaling. Sustained JNK activation by full-length Daxx the binding site for the ASK1 inhibitor thioredoxin, a reduction/
was observed only when active ASK1 was expressed (Fig. 4A), oxidation-regulatory protein (17). Thus, the polyubiquitin tail may
indicating that Daxx-dependent JNK activation is mediated also prevent thioredoxin from interacting with ASK1. Alternatively,
through ASK1. When the K63 ubiquitination-deficient Daxx K63-linked polyubiquitin may recruit an activating cofactor(s), such
mutant K122R was expressed in cells, TNF-a–induced JNK as TNF-associated factor 2 (18), critical for sustained ASK1 kinase
Figure 3. ASK1-dependent Daxx phosphorylation is required for K63-linked ubiquitin conjugation to Daxx. A, ASK1-dependent phosphorylation is required for
Daxx K63-linked ubiquitination. Daxx was immunoprecipitated with anti-FLAG antibody and the precipitated materials were subjected to immunoblotting with anti-Myc or
anti-FLAG antibodies. B, phosphorylated Daxx is K63-linked polyubiquitinated. FLAG-Daxx was coexpressed with Myc-Ub (63K or 48K) and ASK1-HA (wild-type,
kinase-defective, or its constitutive active mutant DN; ref. 17). Cell lysates were subjected to immunoprecipitation with anti-phosphorylated Daxx antibody followed by
immunoblotting with anti-Myc and anti-FLAG antibodies.
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Figure 4. TNF-a–dependent JNK activation and apoptosis require K63-linked polyubiquitination of Daxx. A, Daxx-dependent sustained JNK activation is
ASK1-dependent. HeLa cell extracts were prepared and analyzed for the expression levels of phosphorylated JNK, total JNK, Daxx, and HA-ASK1 by immunoblotting.
B, K122 in Daxx is critical for TNF-a–induced sustained JNK activation. Two days posttransfection, HeLa cells were incubated with TNF-a (0, 1, or 5 ng/mL) for
18 h. C, Daxx K122 is essential for TNF-a–induced apoptosis. After 48 h of transfection, MCF7 cells were treated with TNF-a. The expression levels of cleaved
poly(ADP-ribose) polymerase (PARP ), which is an indicator of apoptosis, FLAG-Daxx, and tubulin were determined by immunoblotting. D, role of K63-linked
polyubiquitination of Daxx in TNF-a signaling pathway. See text for details.
activity. The precise molecular mechanism for how Daxx K63- polyubiquitination at Lys122. Polyubiquitination is not required for
linked ubiquitination activates ASK1 remains to be elucidated. interaction with ASK1 but is essential for ASK1 activation. These
TNF-a signaling involves TNF-associated factor 2 phosphoryla- findings establish a physiological significance to the network of
tion followed by K63-linked ubiquitination (19). Here, we show that Daxx-ASK1-JNK signaling in TNF-a–dependent cell death in which
phosphorylation induced K63-linked ubiquitination of Daxx plays a the K63-linked polyubiquitin tail on Daxx functions as a molecular
critical role in the Daxx-ASK1 positive feedback loop (Fig. 4D). switch for ASK1 activation.
Depletion of Daxx in cells produces resistance to cell death induced
by UV irradiation and oxidative stress and an impaired JNK Disclosure of Potential Conflicts of Interest
activation (20), suggesting that Daxx plays a critical role on JNK-
induced apoptosis. No potential conflicts of interest were disclosed.
Daxx is essential for the sustained activation of JNK and TNF-a–
induced apoptosis in cells (4). ASK1 is required for sustained Acknowledgments
activation of JNK/p38 and apoptosis (21). When ASK1 is activated Received 6/16/09; revised 8/10/09; accepted 8/19/09; published OnlineFirst 9/29/09.
by TNF receptor signaling, it phosphorylates Daxx at Ser176 and Grant support: NIH grant R01CA98666 (N. Horikoshi).
Ser184. This phosphorylation stabilizes Daxx due to a reduced K48- The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
linked polyubiquitination content causing cellular Daxx levels with 18 U.S.C. Section 1734 solely to indicate this fact.
increase. Phosphorylated Daxx is then modified by K63-linked We thank Drs. Helen Piwnica-Worms and Zhijian J. Chen for Ub constructs.
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K63-Linked Polyubiquitination on Daxx Activates ASK1
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