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The DEAD box RNA helicase DDX42 is an intrinsic inhibitor of positive-strand RNA viruses.
EMBO Rep, 23(11):e54061.
Genome-wide screens are powerful approaches to unravel regulators of viralinfections. Here, a CRISPR screen identifies the RNA helicase DDX42 as anintrinsic antiviral inhibitor of HIV-1. Depletion of endogenous DDX42 increasesHIV-1 DNA accumulation and infection in cell lines and primary cells. DDX42overexpression inhibits HIV-1 infection, whereas expression of adominant-negative mutant increases infection. Importantly, DDX42 also restrictsLINE-1 retrotransposition and infection with other retroviruses andpositive-strand RNA viruses, including CHIKV and SARS-CoV-2. However, DDX42 doesnot impact the replication of several negative-strand RNA viruses, arguingagainst an unspecific effect on target cells, which is confirmed by RNA-seqanalysis. Proximity ligation assays show DDX42 in the vicinity of viral elements,and cross-linking RNA immunoprecipitation confirms a specific interaction ofDDX42 with RNAs from sensitive viruses. Moreover, recombinant DDX42 inhibitsHIV-1 reverse transcription in vitro. Together, our data strongly suggest adirect mode of action of DDX42 on viral ribonucleoprotein complexes. Our resultsidentify DDX42 as an intrinsic viral inhibitor, opening new perspectives totarget the life cycle of numerous RNA viruses.
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