Distinct antiviral roles for human 2',5'-oligoadenylate synthetase family members against dengue virus infection.
The 2',5'-oligoadenylate synthetase (OAS) and its downstream effector RNase L play important roles in host defense against virus infection. Oas1b, one of the eight Oas1 genes in the mouse genome, has been identified as a murine flavivirus-resistance gene. Four genes, OAS1, OAS2, OAS3, and OAS-like (OASL), have been identified in the human OAS gene family, and 10 isoforms, including OAS1 (p42, p44, p46, p48, and p52), OAS2 (p69 and p71), OAS3 (p100), and OASL (p30 and p59) can be generated by alternative splicing. In this study, we determined the role of the human OAS/RNase L pathway in host defense against dengue virus (DEN) infection and assessed the antiviral potential of each isoform in the human OAS family. DEN replication was reduced by overexpression and enhanced by knockdown of RNase L expression, indicating a protective role for RNase L against DEN replication in human cells. The human OAS1 p42, OAS1 p46, and OAS3 p100, but not the other OAS isoforms, blocked DEN replication via an RNase L-dependent mechanism. Furthermore, the anti-DEN activities of these three OAS isoforms correlated with their ability to trigger RNase L activation in DEN-infected cells. Thus, OAS1 p42/p46 and OAS3 p100 are likely to contribute to host defense against DEN infection and play a role in determining the outcomes of DEN disease severity.
Lin
Ren-Jye
RJ
Institute of Biomedical Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Yu
Han-Pang
HP
Chang
Bi-Lan
BL
Tang
Wei-Chun
WC
Liao
Ching-Len
CL
Lin
Yi-Ling
YL
D015088:2',5'-Oligoadenylate Synthetase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003715:Dengue / Q000201:enzymology* / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D003716:Dengue Virus / Q000276:immunology*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D005810:Multigene Family; D014775:Virus Activation / Q000276:immunology
D007527:Isoenzymes; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease