FTSJ3 is an RNA 2′-O-methyltransferase recruited by HIV to avoid innate immune sensing

Abstract : In mammals, 2'-O-methylation of RNA is a molecular signature by which the cellular innate immune system distinguishes endogenous from exogenous messenger RNA1-3. However, the molecular functions of RNA 2'-O-methylation are not well understood. Here we have purified TAR RNA-binding protein (TRBP) and its interacting partners and identified a DICER-independent TRBP complex containing FTSJ3, a putative 2'-O-methyltransferase (2'O-MTase). In vitro and ex vivo experiments show that FTSJ3 is a 2'O-MTase that is recruited to HIV RNA through TRBP. Using RiboMethSeq analysis4, we identified predominantly FTSJ3-dependent 2'-O-methylations at specific residues on the viral genome. HIV-1 viruses produced in FTSJ3 knockdown cells show reduced 2'-O-methylation and trigger expression of type 1 interferons (IFNs) in human dendritic cells through the RNA sensor MDA5. This induction of IFN-α and IFN-β leads to a reduction in HIV expression. We have identified an unexpected mechanism used by HIV-1 to evade innate immune recognition: the recruitment of the TRBP-FTSJ3 complex to viral RNA and its 2'-O-methylation.
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Submitted on : Tuesday, January 15, 2019 - 1:29:08 PM
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Mathieu Ringeard, Virginie Marchand, Etienne Decroly, Yuri Motorin, Yamina Bennasser. FTSJ3 is an RNA 2′-O-methyltransferase recruited by HIV to avoid innate immune sensing. Nature, Nature Publishing Group, 2019, 565, pp.500-504. ⟨10.1038/s41586-018-0841-4⟩. ⟨hal-01981983⟩



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