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

作者：Kitamura M^*; Kato H; Saito Y; Nakajima S; Takahashi S; Johno H; Gu L; Katoh R

来源：Cell Death and Differentiation, 2011, 18(12): 1876-1888.

DOI：10.1038/cdd.2011.63

• 3 '-deoxyadenosine
• cordycepin
• unfolded protein response
• apoptosis
• IRE1
• eIF2 alpha

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 eIF2 alpha signaling without affecting PERK activity. It was associated with depression of GADD34 that dephosphorylates eIF2 alpha, and dephosphorylation of eIF2 alpha by salubrinal mimicked the anti-apoptotic effect of 3 '-deoxyadenosine. Unexpectedly, although 3 '-deoxyadenosine caused activation of eIF2 alpha, 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. Cell Death and Differentiation (2011) 18, 1876-1888; doi:10.1038/cdd.2011.63; published online 20 May 2011

• 出版日期2011-12