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Review
. 2017 Apr 3;9(4):a023580.
doi: 10.1101/cshperspect.a023580.

Prion-Like Polymerization in Immunity and Inflammation

Xin Cai  1 , Hui Xu  1 , Zhijian J Chen  1   2
Affiliations
Review

Prion-Like Polymerization in Immunity and Inflammation

Xin Cai et al. Cold Spring Harb Perspect Biol. .

Abstract

The innate immune system relies on receptors that sense common signs of infection to trigger a robust host-defense response. Receptors such as RIG-I and NLRP3 activate downstream adaptors mitochondrial antiviral signaling (MAVS) and apoptosis-associated speck-like protein (ASC), respectively, to propagate immune and inflammatory signaling. Recent studies have indicated that both MAVS and ASC form functional prion-like polymers to propagate immune signaling. Here, we summarize the biochemical, genetic, and structural studies that characterize the prion-like behavior of MAVS and ASC in their respective signaling pathways. We then discuss prion-like polymerization as an evolutionarily conserved mechanism of signal transduction in innate immunity in light of the similarity between the NLRP3-ASC, the NLRP3-ASC pathway in mammals, and the NWD2-HET-s pathway in fungi. We conclude by outlining the unique advantages to signaling through functional prions and potential future directions in the field.

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Figures

Figure 1.
Figure 1.
Cartoon depictions of the sensors, adaptors, and effectors in the mitochondrial antiviral signaling (MAVS)-dependent antiviral and apoptosis-associated speck-like protein (ASC)-dependent inflammasome pathways. Both MAVS and ASC serve as key adaptor proteins that relay multiple upstream signals to downstream effectors. The cytosolic RNA sensor RIG-I activates the MAVS protein to induce the production of interferon through the transcription factor IRF3 and NF-κB. Similarly, NLRP3 activates the adaptor ASC to produce proinflammatory cytokines such as IL-1β. Caspase-1 activation also leads to cell death (pyroptosis).
Figure 2.
Figure 2.
A proposed model for mitochondrial antiviral signaling (MAVS) activation by RIG-I-induced polymerization. Detection of viral 5′-ppp RNA or double-stranded (ds) RNA by RIG-I triggers a conformational change that exposes the N-terminal tandem caspase activation and recruitment domains (CARDs) of RIG-I (RIG-I 2CARD). RIG-I 2CARD then binds to K63-linked polyubiquitin chains, which facilitate the formation of a RIG-I tetramer. The RIG-I 2CARD tetramer interacts with MAVS CARD, providing a template to initiate the nucleation of a MAVS CARD filament. The MAVS CARD filament recruits additional MAVS CARD to form long filaments on the surface of the mitochondrial outer membrane. The MAVS filaments are competent in activating downstream signaling cascades to induce type-I interferons and other antiviral effectors. The models of RIG-I CARD/Ub/MAVS CARD complex and MAVS filaments are built based on PDB 4NQK, 4P4H, 2VGQ, and EMD-6428.
Figure 3.
Figure 3.
Homologous mammalian and fungal host-defense pathways that signal through prion conversion. In mammals, receptors such as NLRP3 sense pathogen invasion or cell damage to rapidly convert its downstream apoptosis-associated speck-like protein (ASC) into its active prion form, which then leads to cytokine secretion and cell death to protect the host. A homologous pathway is present in filamentous fungi, where activated NWD2 receptor converts the HET-S/s protein into a prion to induce cell death. The fungal NWD2-HET-S/s pathway is remarkably similar to the mammalian NLRP3-ASC pathway in both function and domain organization, suggesting that signaling through self-perpetuating protein conformations for host defense and cell-fate determination is conserved from fungi to mammals.
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