Characterization of human phosphodiesterase 12 and identification of a novel 2鈥?5鈥?oligoadenylate nuclease - The ectonucleotide pyrophosphatase/phosphodiesterase 1

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• 作者：Jesper B. Poulsen ^jbp@mb.au.dk ; Kasper R. Andersen¹ ; ^{kasper@mit.edu} ; Karina H. Kjæ ; r ^knk@mb.au.dk ; Anna L. Vestergaard² ; ^{alve@fi.au.dk} ; Just Justesen ^jj@mb.au.dk ; Pia M. Martensen ; ^pmm@mb.au.dk
• 关键词：5&prime ; -triphosphorylated ; 2&prime ; -5&prime ; -linked oligoadenylate polyribonucleotides (2-5As) ; 5&prime ; -dephosphorylated 2-5As (2-5A core molecules) ; 2-5A catabolism ; Phosphodiesterase 12 ; 2&prime ; -5&prime ; oligoadenylate nucleases
• 刊名：Biochimie
• 出版年：2012
• 期刊代码：24_03009084
• 类别：bio
• 出版时间：May, 2012
• 卷：94
• 期：5
• 页码：1098-1107
• 文件大小：1185 K

摘要

The vertebrate 2-5A system is part of the innate immune response and central to cellular antiviral activities. Upon activation by viral double-stranded RNA, 5鈥?triphosphorylated, 2鈥?5鈥?linked oligoadenylate polyribonucleotides (2-5As) are synthesized by one of several 2鈥?5鈥?oligoadenylate synthetases. The 2-5As bind and activate RNase L, an unspecific endoribonuclease, resulting in viral and cellular RNA decay. Given that most endogenous RNAs are degraded by RNase L, continued enzyme activity will eventually lead to cell growth arrest and cell death. This is averted, when 2-5As and their 5鈥?dephosphorylated forms, the so-called 2-5A core molecules, are cleaved and thus inactivated by 2鈥?5鈥?specific nuclease(s), e.g. phosphodiesterase 12, thereby turning RNase L into its latent form. In this study, we have characterized the human phosphodiesterase 12 in聽vitro focusing on its ability to degrade 2-5As and 2-5A core molecules. We have found that the enzyme activity is distributive and is influenced by temperature, pH and divalent cations. This allowed us to determine V_max and K_m kinetic parameters for the enzyme. We have also identified a novel 2鈥?5鈥?oligoadenylate nuclease; the human plasma membrane-bound ectonucleotide pyrophosphatase/phosphodiesterase 1, suggesting that 2-5A catabolism may be a multienzyme-regulated process.