Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Pattern recognition receptors (PRRs) are crucial for detecting pathogens and initiating immune responses.
• While microbial PRR ligands are well-studied, the role of endogenous ligands in PRR activation is largely unexplored.
• RIG-I-like receptors (RLRs) are key sensors of viral RNA.

Purpose of the Study:

• To characterize endogenous RNA ligands that activate RIG-I-like receptors (RLRs) during viral infections.
• To investigate the mechanism by which Y RNAs engage RLRs.
• To determine the role of HIV-1 infection in modulating endogenous RNA immunogenicity.

Main Methods:

• Analysis of RNA transcribed by RNA polymerase III (Pol3) during viral infections.
• Assessment of Y RNA engagement with RLRs, focusing on secondary structure and 5'-triphosphate presence.
• In vitro and in vivo studies examining HIV-1 VPR-dependent regulation of DUSP11 and its effect on cellular RNA 5'-triphosphorylation.

Main Results:

• Several Pol3-transcribed RNAs, notably Y RNAs, were identified as endogenous ligands engaging RLRs during viral infections.
• Y RNA sensing by RLRs depends on mimicking viral secondary structures and possessing a 5'-triphosphate group.
• HIV-1 infection, via VPR, downregulates DUSP11, altering cellular RNA 5'-triphosphorylation and enabling Y RNA immunogenicity.

Conclusions:

• Endogenous RNAs significantly contribute to antiviral immunity by engaging RLRs.
• Y RNAs are critical endogenous ligands for RLRs, acting as danger signals when mimicking viral RNA features.
• The pathway involving DUSP11 regulation by HIV-1 highlights a novel mechanism impacting host antiviral defense.