Dengue virus exploits the host tRNA epitranscriptome to promote viral replication

Area of Science:

• Virology
• Molecular Biology
• Epitranscriptomics

Background:

• The epitranscriptome, comprising over 40-50 RNA modifications, plays a critical role in regulating gene expression post-transcriptionally.
• Flaviviruses, including dengue virus, are known to manipulate host cell machinery for their replication.

Approach:

• Investigated the role of tRNA-modifying enzyme ALKBH1 and its products 5-formylcytidine (f⁵C) and 2'-O-methyl-5-formylcytidine (f⁵Cm) during dengue virus infection in human Huh-7 cells.
• Utilized ALKBH1 knockdown and overexpression models to assess their impact on viral protein levels (NS3, NS5) and replication.
• Analyzed the effect of ALKBH1 modulation on tRNA modification levels and codon-biased translation.

Key Points:

• Dengue virus infection reduces ALKBH1, f⁵C, and f⁵Cm levels early in infection.
• ALKBH1 acts as a host restriction factor; its knockdown enhances viral NS3 protein levels and replication, while overexpression inhibits them.
• Viral NS5 protein increases f⁵Cm levels late in infection, impacting translation of UUA-deficient transcripts, many with pro-viral functions.

Conclusions:

• A dynamic ALKBH1/f⁵Cm axis is crucial during dengue infection.
• Viruses remodel the host proteome through tRNA reprogramming and codon-biased translation.
• ALKBH1 is a key host restriction factor against flavivirus infection by maintaining tRNA epitranscriptomic integrity.