MAVS Forms Functional Prion-Like Aggregates To Activate and Propagate Antiviral Innate Immune Response

By F. Hou, Lijun Sun, Hui Zheng, B. Skaug, Q. Jiang, Zhijian J. Chen. Cell, 2011

1,257 citations recorded by the source corpus.

SUMMARY In response to viral infection, RIG-I–like RNA helicases bind to viral RNA and activate the mitochondrial protein MAVS, which in turn activates the transcription factors IRF3 and NF-κB to induce type-I interferons. We have previously shown that RIG-I binds to unanchored lysine-63 (K63) polyubiquitin chains and that this binding is important for MAVS activation; however, the mechanism underlying MAVS activation is not understood. Here we show that viral infection induces the formation of very large MAVS aggregates, which potently activate IRF3 in the cytosol. We find that a fraction of recombinant MAVS protein forms fibrils capable of activating IRF3. Remarkably, the MAVS fibrils behave like prions and effectively convert endogenous MAVS into functional aggregates. We also show that, in the presence of K63 ubiquitin chains, RIG-I catalyzes the conversion of MAVS on the mitochondrial membrane to prion-like aggregates. These results suggest that a prion-like conformational switch of MAVS activates and propagates the antiviral signaling cascade.

Subfields: Immunology, Molecular Biology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/99a5a255c28e607393707e747f54958e048c512f

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Citations in the corpus

Structural insights into RNA recognition by RIG-I (2011, positive): “in the cell and activate IPS-1 by promoting IPS-1 oligomerization (Baril et al., 2009; Hou et al., 2011; Tang and Wang, 2009).”
Signaling in innate immunity and inflammation. (2012, background): “Subsequently, MAVS forms large aggregates (Hou et al. 2011) that stimulate MAPK activation and transcription induced by IRF3, IRF7, and NF-kB.”
The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis (2012, neutral): “In addition, this DD superfamily scaffold exhibits functional characteristics akin to amyloids and prions in their abilities to seed and to propagate (Hou et al., 2011).”
Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation (2015, positive): “To understand how MAVS activates IRF3, we used cell-free assays that recapitulate IRF3 and IkBa activation by different upstream activators (8, 11, 14).”
Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders (2017, methodology): “ 4 G), a method for detecting large protein oligomers in studying prions (Alberti et al., 2009; Hou et al., 2011).”
Selective RNA targeting and regulated signaling by RIG-I is controlled by coordination of RNA and ATP binding (2016, positive): “The RNA-bound RIG-I is now competent to bind ATP, which is involved in presenting the CARDs for a productive interaction with MAVS, thereby stimulating subsequent downstream signaling (11,15,21).”
Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection (2021, background): “This then leads to the stimulation of mitochondrial antiviral signaling protein on the mitochondrial membrane to activate IRF3 or NF-κB (p50/p65) and promote their nuclear translocation to induce the production of IFN-I and other antiviral molecules such as inflammatory cytokines (85) (Fig.”
Innate Immune Pattern Recognition: A Cell Biological Perspective (2015, neutral): “Once activated, MAVS undergoes CARD-dependent self-polymerization, creating prion-like aggregates that are important for signal transmission (204).”
The ubiquitin code. (2012, background): “Lys63-linked chains activate IKK by promoting its binding to the upstream TAK1 that distinct types of ubiquitin topologies, i.e., Met1-, Lys11/Lys63-, Lys63-, or Lys48-linked chains, regulate signaling through inhibitor degradation, proteasomal processing, allosteric”
The adapter MAVS promotes NLRP3 mitochondrial localization and inflammasome activation (2013, positive): “How might this occur? A recent study suggests that virus infection induces the formation of detergent-resistant, fibril-like, high molecular weight aggregates of the MAVS protein and that these aggregates are potent activators of IRF3 (Hou et al., 2011).”
ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA (2015, background): “Multiple Ub-2CARD complexes assemble to form a nucleation site for the polymerization of mitochondrial antiviral-signaling adaptor protein (MAVS) into long helical filaments (Hou et al., 2011; Wu et al., 2014; Xu et al., 2014).”
NF-κB, the first quarter-century: remarkable progress and outstanding questions. (2012, background): “Aggregative induction of the NF-kB signaling pathways is most strikingly illustrated by the recent description of the ability of the RLR adapter MAVS to form large fibril-like aggregates upon viral infection (Hou et al. 2011).”
A structure-based model of RIG-I activation. (2012, background): “RNA- and polyubiquitin-bound RIG-I-induced aggregation of MAVS on the mitochondrial membrane (Hou et al. 2011; Jiang et al. 2012), aided by the regulator of mitochondrial fusion, MFN1 (Onoguchi et al. 2010), leads to activation of kinases IKK and TBK1, which, in turn, mobilize tion of the larger…”