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

Genome Biol. 2020 Sep 1;21(1):228. doi: 10.1186/s13059-020-02150-9.


Background: The central nervous system (CNS) is vulnerable to viral infection, yet few host factors in the CNS are known to defend against invasion by neurotropic viruses. Long noncoding RNAs (lncRNAs) have been revealed to play critical roles in a wide variety of biological processes and are highly abundant in the mammalian brain, but their roles in defending against invasion of pathogens into the CNS remain unclear.

Results: We report here that multiple neurotropic viruses, including rabies virus, vesicular stomatitis virus, Semliki Forest virus, and herpes simplex virus 1, elicit the neuronal expression of a host-encoded lncRNA EDAL. EDAL inhibits the replication of these neurotropic viruses in neuronal cells and rabies virus 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 regulates the transcription of Pcp4l1 encoding a 10-kDa peptide, which inhibits the replication of multiple neurotropic viruses.

Conclusions: Our findings show that a neuronal lncRNA can exert an effective antiviral function via blocking a specific O-GlcNAcylation that determines EZH2 lysosomal degradation, rather than the traditional interferon-dependent pathway.

Keywords: EZH2, lncRNA, neurotropic virus, O-GlcNAcylation, PCP4L1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System Infections / metabolism*
  • Central Nervous System Infections / virology
  • Chlorocebus aethiops
  • Enhancer of Zeste Homolog 2 Protein / metabolism*
  • Female
  • Host-Pathogen Interactions*
  • Indoles
  • Lysosomes / metabolism
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / metabolism
  • Pyridones
  • RNA, Long Noncoding / metabolism*
  • Rabies / metabolism
  • Rabies virus / pathogenicity
  • Vero Cells
  • Virus Diseases / metabolism*
  • Virus Replication


  • GSK-2816126
  • Indoles
  • Nerve Tissue Proteins
  • Pcp4l1 protein, mouse
  • Pyridones
  • RNA, Long Noncoding
  • Enhancer of Zeste Homolog 2 Protein
  • Ezh2 protein, mouse