Abstract
The unfolded protein response (UPR) is involved in a diverse range of pathologies triggered by endoplasmic reticulum (ER) stress. Endeavor to seek selective regulators of the UPR is a promising challenge towards therapeutic intervention in ER stress-related disorders. In the present report, we describe aberrant, differential and bidirectional regulation of the UPR by 3′-deoxyadenosine (cordycepin) towards cell survival. 3′-Deoxyadenosine blocked ER stress-induced apoptosis via inhibiting the IRE1–JNK pro-apoptotic pathway. 3′-Deoxyadenosine also inhibited apoptosis through reinforcement of the pro-survival eIF2α signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2α, and dephosphorylation of eIF2α by salubrinal mimicked the anti-apoptotic effect of 3′-deoxyadenosine. Unexpectedly, although 3′-deoxyadenosine caused activation of eIF2α, it inhibited downstream pro-apoptotic events including induction of ATF4 and expression of CHOP. Cooperation of adenosine transporter and A3 adenosine receptor, but not A1/A2 receptors, mediated the pluripotent effects of 3′-deoxyadenosine. In mice, ER stress caused activation of JNK, expression of CHOP and induction of apoptosis in renal tubules. The apoptosis was significantly attenuated by administration with 3′-deoxyadenosine, and it was correlated with blunted induction of JNK and CHOP in the kidney. These results disclosed atypical pro-survival regulation of the UPR by 3′-deoxyadenosine, which may be advantageous for the treatment of intractable, ER stress-related disorders.
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Abbreviations
- ER:
-
endoplasmic reticulum
- UPR:
-
unfolded protein response
- ATF6:
-
activating transcription factor 6
- IRE1:
-
inositol-requiring enzyme 1
- PERK:
-
PKR-like ER kinase
- XBP1:
-
X-box-binding protein 1
- ERSE:
-
ER stress response element
- UPRE:
-
UPR element
- GRP78:
-
78 kDa glucose-regulated protein
- ORP150:
-
150 kDa oxygen-regulated protein
- ERAD:
-
ER-associated degradation
- Edem1:
-
ER degradation enhancing α-mannosidase-like protein 1
- eIF2α:
-
eukaryotic translation initiation factor 2α
- CHOP:
-
CCAAT/enhancer-binding protein-homologous protein
- GADD34:
-
growth arrest and DNA damage gene 34
- ASK1:
-
apoptosis signal-regulating kinase 1
- JNK:
-
c-Jun N-terminal kinase
- DTT:
-
dithiothreitol
- SubAB:
-
subtilase cytotoxin
- DPSPX:
-
1,3-dipropyl-8-(p-sulfophenyl)xanthine
- NBTI:
-
S-(4-nitrobenzyl)-6-thioinosine
- SEAP:
-
secreted alkaline phosphatase
- SV40:
-
simian virus 40
- GAPDH:
-
glyceraldehyde-3-phosphate dehydrogenase
- EF-1α:
-
elongation factor-1α
- CMV:
-
cytomegalovirus
- TUNEL:
-
terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling
- FBS:
-
fetal bovine serum
- DAPI:
-
4′-6-diamidino-2-phenylindole
- XBP1(U):
-
unspliced form of XBP1
- XBP1(S):
-
spliced form of XBP1
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Acknowledgements
We thank Dr. Laurie H. Glimcher (Harvard Medical School), Dr. Ronald C. Wek (Indiana University School of Medicine), Dr. Takahiro Taira (University of Yamanashi), Dr. Takao Iwawaki (RIKEN), Dr. Takeshi Omasa (Osaka University), Dr. Pierre Fafournoux (INRA de Theix), Dr. Amy S Lee (University of South California), Dr. Satoshi Ogawa (Kanazawa University), Dr. Nobuko Hosokawa (Kyoto University), Dr. Jianxin Sun (New Jersey Medical School), Dr. Kazunori Imaizumi (University of Miyazaki) and Dr. David Ron (New York University School of Medicine) for providing us with plasmids. We also appreciate Dr. James Paton (University of Adelaide) for a kind gift of SubAB, and Miss Yukiko Kanayama and Mrs. Mikiko Yoda (University of Yamanashi) for technical assistance. This work was supported by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (No.20390235) to M Kitamura, and in part by the Global COE Program and Smoking Research Foundation.
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Kitamura, M., Kato, H., Saito, Y. et al. Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3′-deoxyadenosine. Cell Death Differ 18, 1876–1888 (2011). https://doi.org/10.1038/cdd.2011.63
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DOI: https://doi.org/10.1038/cdd.2011.63
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