Abstract
In response to virus infection, RIG-I-like receptors (RLRs) sense virus RNA and induce MAVS to form prion-like aggregates to further propagate antiviral signalling. Although monomeric MAVS recombinant protein can assemble into prion-like filaments spontaneously in vitro, endogenous MAVS in cells is prevented from aggregation until viral infection. The mechanism preventing cellular MAVS from spontaneous aggregation is unclear. Here we show that multiple N-terminal truncated isoforms of MAVS are essential in preventing full-length MAVS from spontaneous aggregation through transmembrane domain-mediated homotypic interaction. Without these shorter isoforms, full-length MAVS is prone to spontaneous aggregation and Nix-mediated mitophagic degradation. In the absence of N-terminally truncated forms, blocking Nix-mediated mitophagy stabilizes full-length MAVS, which aggregates spontaneously and induces the subsequent expression of type I interferon and other proinflammatory cytokines. Our data thus uncover an important mechanism preventing spontaneous aggregation of endogenous MAVS to avoid accidental activation of antiviral innate immune signalling.
Highlights
In response to virus infection, RIG-I-like receptors (RLRs) sense virus RNA and induce MAVS to form prion-like aggregates to further propagate antiviral signalling
The truncated isoform is separated from full-length MAVS when the latter forms functional prion-like aggregates[14]
Our results suggested that endogenous MAVS(M2-6L) is subjected to autophagy-mediated degradation due to its spontaneous aggregation, which is a result of the absence of N-terminally truncated isoforms
Summary
In response to virus infection, RIG-I-like receptors (RLRs) sense virus RNA and induce MAVS to form prion-like aggregates to further propagate antiviral signalling. We show that multiple N-terminal truncated isoforms of MAVS are essential in preventing full-length MAVS from spontaneous aggregation through transmembrane domain-mediated homotypic interaction. In the absence of N-terminally truncated forms, blocking Nix-mediated mitophagy stabilizes full-length MAVS, which aggregates spontaneously and induces the subsequent expression of type I interferon and other proinflammatory cytokines. The TM domain tethers MAVS to the mitochondria, which is critical for its antiviral function but the underlying mechanism is unclear[8] Both recombinant MAVSDTM and isolated CARD can form prion-like aggregates spontaneously in vitro, but endogenous MAVS in cells remains monomeric and quiescent until virus infection[14], indicating the involvement of a critical mechanism that prevents endogenous MAVS from spontaneous aggregation. Our studies uncover a mechanism to prevent MAVS spontaneous aggregation in cells, which avoids the misfiring of innate immune response for potential detrimental inflammation, and it might provide a general mechanism in preventing spontaneous aggregation of prion-like proteins in cellular signalling
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