A novel antiviral lncRNA EDAL shields a T309 O-GlcNAcylation site to promote EZH2 degradation

Zhao, L.; Sui, B.; Chen, D.; Liu, W.; Wu, Q.; Tian, B.; Hou, J.; Li, Y.; Liu, S.; Xie, J.; Jiang, H.; Luo, Z.; Lv, L.; Huang, F.; Li, R.; Cui, M.; Zhou, M.; Chen, H.; Fu, Z. F.; Zhang, Y.

doi:10.1101/824813

bioRxiv · 10.1101/824813

A novel antiviral lncRNA EDAL shields a T309 O-GlcNAcylation site to promote EZH2 degradation

Zhao, L.·Sui, B.·Chen, D.·Liu, W.·Wu, Q.·Tian, B.·Hou, J.·Li, Y.·Liu, S.·Xie, J.·Jiang, H.·Luo, Z.·Lv, L.·Huang, F.·Li, R.·Cui, M.·Zhou, M.·Chen, H.·Fu, Z. F.·Zhang, Y.

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Abstract

The central nervous system (CNS) is vulnerable for viral infection, yet few host factors in the CNS are known to defend invasion by neurotropic viruses. We report here that multiple neurotropic viruses, including rabies virus (RABV), vesicular stomatitis virus (VSV), Semliki Forest virus (SFV) and herpes simplex virus 1 (HSV-1), elicit the neuronal expression of a host-encoded lncRNA EDAL. EDAL inhibits the replication of these neurotropic viruses in neuronal cells and RABV infection in mouse brains. EDAL binds to the conserved histone methyltransferase enhancer of zest homolog 2 (EZH2) and specifically causes EZH2 degradation via lysosomes, reducing the cellular H3K27me3 level. The antiviral function of EDAL resides in a 56-nt antiviral substructure through which its 18-nt helix-loop intimately contacts multiple EZH2 sites surrounding T309, a known O-GlcNAcylation site. EDAL positively regulate the transcription of Pcp4l1 encoding a 10 kDa peptide, which inhibits the replication of mutiple neurotropic viruses. Our findings proposed a model in which a neuronal lncRNA can exert an effective antiviral function via blocking a specific O-GlcNAcylation that determines EZH2 lysosomal degradation.

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Zhao, L., Sui, B., Chen, D., Liu, W., Wu, Q., Tian, B., Hou, J., Li, Y., Liu, S., Xie, J., Jiang, H., Luo, Z., Lv, L., Huang, F., Li, R., Cui, M., Zhou, M., Chen, H., Fu, Z. F., Zhang, Y.. 2019-10-30. A novel antiviral lncRNA EDAL shields a T309 O-GlcNAcylation site to promote EZH2 degradation. https://doi.org/10.1101/824813

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