期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 279, 期 36, 页码 37832-37841出版社
ELSEVIER
DOI: 10.1074/jbc.M400089200
关键词
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The 2-5A system is one of the major pathways for antiviral and antitumor functions that can be induced by interferons (IFNs). The 2-5A system is modulated by 5'-triphosphorylated, 2',5'-phosphodiester-linked oligoadenylates ( 2-5A), which are synthesized by 2', 5'-oligoadenylate synthetases (2', 5'-OASs), inactivated by 5'-phosphatase and completely degraded by 2'-phosphodiesterase (2'-PDE). Generated 2 - 5A activates 2 - 5A-dependent endoribonuclease, RNase L, which induces RNA degradation in cells and finally apoptosis. Although 2', 5'-OASs and RNase L have been molecularly cloned and studied well, the identification of 2'-PDE has remained elusive. Here, we describe the first identification of 2'-PDE, the third key enzyme of the 2 - 5A system. We found a putative 2'-PDE band on SDS-PAGE by successive six-step chromatographies from ammonium sulfate precipitates of bovine liver and identified a partial amino acid sequence of the human 2'-PDE by mass spectrometry. Based on the full-length sequence of the human 2'-PDE obtained by in silico expressed sequence tag assembly, the gene was cloned by reverse transcription-PCR. The recombinant human 2'-PDE expressed in mammalian cells certainly cleaved the 2', 5'-phosphodiester bond of 2 - 5A trimer and 2 - 5A analogs. Because no sequences with high homology to this human 2'-PDE were found, the human 2'-PDE was considered to be a unique enzyme without isoform. Suppression of 2'-PDE by a small interfering RNA and a 2'-PDE inhibitor resulted in significant reduction of viral replication, whereas overexpression of 2'-PDE protected cells from IFN-induced antiproliferative activity. These observations identify 2'-PDE as a key regulator of the 2 - 5A system and as a potential novel target for antiviral and antitumor treatments.
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