Interference of DNAJB6/MRJ Isoform Switch by Morpholino Inhibits Replication of HIV-1 and RSV

Shih-Han Ko; Yi-Jen Liau; Ya-Hui Chi; Mei-Ju Lai; Yu-Ping Chiang; Chun-Yi Lu; Luan-Yin Chang; Woan-Yuh Tarn; Li-Min Huang

doi:10.1016/j.omtn.2018.12.001

Interference of DNAJB6/MRJ Isoform Switch by Morpholino Inhibits Replication of HIV-1 and RSV

Mol Ther Nucleic Acids. 2019 Mar 1:14:251-261. doi: 10.1016/j.omtn.2018.12.001. Epub 2018 Dec 10.

Authors

Shih-Han Ko¹, Yi-Jen Liau², Ya-Hui Chi³, Mei-Ju Lai², Yu-Ping Chiang², Chun-Yi Lu², Luan-Yin Chang², Woan-Yuh Tarn⁴, Li-Min Huang⁵

Affiliations

¹ Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan.
² Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan.
³ Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan. Electronic address: wtarn@ibms.sinica.edu.tw.
⁵ Department of Pediatrics, National Taiwan University Children's Hospital, National Taiwan University College of Medicine, Taipei 10002, Taiwan. Electronic address: lmhuang@ntu.edu.tw.

Abstract

The molecular chaperon MRJ (DNAJB6) exhibits two splice isoforms that have different roles in human viral infection, but the regulatory mechanism of MRJ isoform expression is yet unclear. In this study, we show that reduction of the polyadenylation factor CstF64 was correlated with the increase of the MRJ large isoform (MRJ-L) in human macrophages and elucidate the mechanism underlying CstF64-modulated MRJ isoform expression. Moreover, we exploited an antisense strategy targeting MRJ-L for virus replication. A morpholino oligonucleotide complementary to the 5' splice site of MRJ intron 8 downregulated MRJ-L expression and suppressed the replication of not only HIV-1 but also respiratory syncytial virus (RSV). We demonstrated that downregulation of the MRJ-L level reduced HIV-1 replication as well as the subgenomic mRNA and viral production of RSV. The present findings that two human health-threatening viruses take advantage of MRJ-L for infection suggest MRJ-L as a potential target for broad-spectrum antiviral strategy.

Keywords: CstF64; DNAJB6; HIV-1; MRJ; RSV; polyadenylation; splicing.