Schlafen14 Impairs HIV-1 Expression in a Codon Usage-Dependent Manner

Area of Science:

• Molecular Biology
• Virology
• Biochemistry

Background:

• Schlafen (SLFN) proteins are interferon-induced and regulate translation.
• SLFN14 associates with ribosomes and exhibits nuclease activity against various RNAs in vitro.
• The precise role of SLFN14 in cellular translation remains elusive.

Purpose of the Study:

• To investigate the role of SLFN14 in the expression of messenger RNAs (mRNAs) enriched in rare codons.
• To determine the impact of SLFN14 on human immunodeficiency virus type 1 (HIV-1) gene expression and replication.
• To elucidate the mechanism by which SLFN14 affects gene expression.

Main Methods:

• Assessed SLFN14's effect on HIV-1 and non-viral gene expression in various cell types, including primary immune cells.
• Utilized codon adaptation index (CAI) to measure synonymous codon usage bias.
• Investigated the necessity of SLFN14's endoribonuclease activity and ribosomal RNA (rRNA) degradation for its function.
• Evaluated the impact of codon optimization on the inhibitory effect of SLFN14.

Main Results:

• SLFN14 regulates gene expression based on codon adaptation index, impacting both viral and non-viral transcripts.
• SLFN14 significantly inhibits HIV-1 replication.
• Codon optimization of HIV-1 Gag transcripts minimized the inhibitory effect of SLFN14.
• SLFN14's endoribonuclease activity and rRNA degradation are crucial for its inhibitory mechanism.

Conclusions:

• SLFN14 impairs the expression of HIV-1 transcripts rich in rare codons in a catalytic-dependent manner.
• SLFN14 acts as a host restriction factor that inhibits HIV-1 replication by targeting codon usage.
• The findings reveal a novel mechanism of viral gene regulation by a host interferon-stimulated gene.