Evidence for age-dependent impairment of antiviral 2',5'-oligoadenylate synthetase/ribonuclease L-system in tissues of rat.
The 2',5'-oligoadenylate system (2-5A system) has an essential role in the establishment of the antiviral state of cells exposed to virus infection. The effects of 2-5A are mediated by a 2-5A-dependent ribonuclease (RNase L) which cleaves viral RNA. A study of 2-5A metabolism in different tissues of rats of different age (newborn: 1-day-old; young adult: 2- to 3-month-old; middle-aged adult: 12-month-old; and old: 32- to 33-month-old) revealed that the activities of the 2-5A metabolic enzymes alter during aging and development. We demonstrate that soluble 2-5A synthetase activity strongly increases after birth, reaching maximal levels in young adult and middle-aged adult animals and then significantly decreases with age; the age-dependent decrease was found also for the nuclear matrix-associated enzyme. In contrast, the activity of 2',3'-exoribonuclease which inactivates 2-5A increases by 3-fold with age. The decrease in 2-5A synthetase activity and increase in 2-5A nuclease activity were found to result in a decrease in the cellular 2-5A content with age. The RNase L which is activated by 2-5A also changes age-dependently. The amount and activity of this enzyme were determined in cross-linking experiments, in nitrocellulose binding assays and in the ribosomal RNA cleavage assay. The livers of old rats displayed a 5- to 6-fold decrease in RNase L activity compared to the adult animal groups, whilst the amount of the enzyme did not change significantly during aging with the exception of a drop by 30% in the nuclear matrix fraction. From these results we conclude that the antiviral activity of the 2-5A system is impaired in old cells with the consequences that virus production cannot be efficiently suppressed.
Pfeifer
K
K
Institut für Physiologische Chemie, Universität, Mainz, Germany.
Ushijima
H
H
Lorenz
B
B
Müller
W E
WE
Schröder
H C
HC
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000378:metabolism; D000375:Aging / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism*; D009843:Oligoribonucleotides / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D014018:Tissue Distribution
D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009843:Oligoribonucleotides; D012367:RNA, Viral; C023505:2',5'-oligoadenylate; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease