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Aberrant, differential and bidirectional regulation of the unfolded protein response towards cell survival by 3'-deoxyadenosine.

Authors: Kitamura, M  Kato, H  Saito, Y  Nakajima, S  Takahashi, S  Johno, H  Gu, L  Katoh, R 
Citation: Kitamura M, etal., Cell Death Differ. 2011 Dec;18(12):1876-88. doi: 10.1038/cdd.2011.63. Epub 2011 May 20.
Pubmed: (View Article at PubMed) PMID:21597460
DOI: Full-text: DOI:10.1038/cdd.2011.63

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 eIF2alpha signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2alpha, and dephosphorylation of eIF2alpha by salubrinal mimicked the anti-apoptotic effect of 3'-deoxyadenosine. Unexpectedly, although 3'-deoxyadenosine caused activation of eIF2alpha, 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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CRRD Object Information
CRRD ID: 10045896
Created: 2015-06-23
Species: All species
Last Modified: 2015-06-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.