Breaching Self-Tolerance to Alu Duplex RNA Underlies MDA5-Mediated Inflammation

Abstract

Aberrant activation of innate immune receptors can cause a spectrum of immune disorders, such as Aicardi-Goutières syndrome (AGS). One such receptor is MDA5, a viral dsRNA sensor that induces antiviral immune response. Using a newly developed RNase-protection/RNA-seq approach, we demonstrate here that constitutive activation of MDA5 in AGS results from the loss of tolerance to cellular dsRNAs formed by Alu retroelements. While wild-type MDA5 cannot efficiently recognize Alu-dsRNAs because of its limited filament formation on imperfect duplexes, AGS variants of MDA5 display reduced sensitivity to duplex structural irregularities, assembling signaling-competent filaments on Alu-dsRNAs. Moreover, we identified an unexpected role of an RNA-rich cellular environment in suppressing aberrant MDA5 oligomerization, highlighting context dependence of self versus non-self discrimination. Overall, our work demonstrates that the increased efficiency of MDA5 in recognizing dsRNA comes at a cost of self-recognition and implicates a unique role of Alu-dsRNAs as virus-like elements that shape the primate immune system.

Double-Stranded RNA Sensors and Modulators in Innate Immunity

“…disfavors enrichment of stimulatory dsRNAs by MDA5 pull-down or by other affinity-based methods (8). By contrast, a conformation-specific method directly utilizing MDA5 filament formation enabled selective isolation of its dsRNA ligands (8).…”

T time for ADAR : ADAR 1 is required for T cell self‐tolerance

“…For example, although patients display a significant ISG signature, the molecular trigger that initiates the type I IFN response is not known. The study by Nakahama and co‐workers now joins other studies suggesting that self‐nucleic acids may trigger autoimmune diseases . Identifying the immunostimulatory self‐RNAs (presumably SINE RNAs or other endogenous RNA species) and investigating the molecular mechanisms by which ADAR1 prevents dsRNAs from activating PRRs could reveal insights into the underlying causes of various autoimmune diseases and clues on how to develop effective therapeutics.…”

Treatments in Aicardi–Goutières syndrome

“…Retroelements are ‘remnants’ of ancient viruses that have become incorporated into the human genome, that now constitute up to 40% of our DNA. Such retroelements were first suggested as a driver of AGS in 2008, with recent papers adding weight to this hypothesis . Salvaging of the Trex1 null mouse phenotype with combination reverse transcriptase inhibitors (RTIs) has been reported, premised on a reduction of immunostimulatory DNA derived through an essential (reverse transcription: RNA>DNA) step in the lifecycle of certain endogenous retroelements (Fig.…”