Prion-Like Polymerization in Immunity and Inflammation

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.

An rpw8 quadruple mutant of Arabidopsis Col-0 is partially compromised in bacterial and fungal resistance

“…In animals and fungi, these HeLo-domain-containing proteins can oligomerise (upon sensing of various signals) causing the HeLo-domain to form a disruptive membrane insertion structure (i.e. poreforming), resulting in cell death (Cai et al, 2017). Based on the presence of a putative Nterminal HeLo domain, MLKL-encoding genes have recently been identified in plants (Mahdi et al, 2019).…”

The AIM2 inflammasome: Sensor of pathogens and cellular perturbations

“…Most of these pathways are involved in innate immunity and may have evolved to enable a robust and rapid response to an insult. 35 Prionization of the signal has been observed for all ASC-containing inflammasome tested so far including the AIM2 inflammasome. 36 Within the AIM2 inflammasome, the PYD of AIM2 drives both filament formation and may facilitate ligand binding.…”

“…This amplification was described for several signaling pathways that use the death fold (such as PYD and CARD) as a recruitment and activation domain. Most of these pathways are involved in innate immunity and may have evolved to enable a robust and rapid response to an insult . Prionization of the signal has been observed for all ASC‐containing inflammasome tested so far including the AIM2 inflammasome …”

Identification of NLR-associated amyloid signaling motifs in filamentous bacteria

“…This signaling mechanism based on the prion principle (self-propagation of protein polymers) is also 52 operating in several immune signaling cascades in mammals, albeit with a different underlying 53 structural basis (Cai et al 2016). In fungi, NLR and their cognate regulated effector proteins are 54 typically encoded by adjacent genes and thus form functional gene pairs or clusters (Daskalov et al 55 2015a; Daskalov et al 2012).…”