Filament assembly underpins the double-stranded DNA specificity of AIM2-like receptors

Abstract

Upon sensing cytosolic- and/or viral double-stranded (ds)DNA, absent-in-melanoma-2 (AIM2)-like-receptors (ALRs) assemble into filamentous signaling platforms to initiate inflammatory responses. The versatile yet critical roles of ALRs in host innate defense are increasingly appreciated; however, the mechanisms by which AIM2 and its related IFI16 specifically recognize dsDNA over other nucleic acids remain poorly understood (i.e. single-stranded (ss)DNA, dsRNA, ssRNA and DNA:RNA hybrid). Here, we find that although AIM2 can interact with various nucleic acids, it preferentially binds to and assembles filaments faster on dsDNA in a duplex length-dependent manner. Moreover, AIM2 oligomers assembled on nucleic acids other than dsDNA not only display less ordered filamentous structures, but also fail to induce the polymerization of downstream ASC. Likewise, although showing broader nucleic acid selectivity than AIM2, IFI16 binds to and oligomerizes most readily on dsDNA in a duplex length-dependent manner. Nevertheless, IFI16 fails to form filaments on single-stranded nucleic acids and does not accelerate the polymerization of ASC regardless of bound nucleic acids. Together, we reveal that filament assembly is integral to nucleic acid distinction by ALRs.

The cytoplasmic sensor, the AIM2 inflammasome: A precise therapeutic target in vascular and metabolic diseases

“…The binding domain of AIM2, PYD, is an essential component for the activation of caspase by dsDNA (Roberts et al, 2009). It is worth mentioning that dsDNA is the only nucleic acid that promotes ASC polymerization because the structure of AIM2-dsDNA is suitable for inducing ASC-PYD assembly (Garg et al, 2023). The filament assembly of AIM2-dsDNA is important both for stable binding with dsDNA and for association with downstream effectors (Garg et al, 2023).…”

“…Qin et al, 2023). AIM2 is a sensor protein within this complex (Garg et al, 2023). The main biological functions of the AIM2 inflammasome include the following.…”

“…As mentioned above, an assembly of the AIM2 inflammasome is initiated and activated by dsDNA (Garg et al, 2023). The binding domain of AIM2, PYD, is an essential component for the activation of caspase by dsDNA (Roberts et al, 2009).…”

“…It is worth mentioning that dsDNA is the only nucleic acid that promotes ASC polymerization because the structure of AIM2–dsDNA is suitable for inducing ASC PYD assembly (Garg et al, 2023). The filament assembly of AIM2–dsDNA is important both for stable binding with dsDNA and for association with downstream effectors (Garg et al, 2023). AIM2‐activating dsDNA occurs for both pathogens and the endogenous DNA fragments produced by nuclear and mitochondrial damage (Sun et al, 2018; Tavris et al, 2023; Yan et al, 2021).…”

“…dsDNA activates the autoinhibited state of AIM2 through the HIN domain. Meanwhile, the substrate dsDNA forms pseudo‐continuous double helices through stacking and serves as an oligomerization platform (Garg et al, 2023; Morrone et al, 2015). Through the AIM2 HIN domain, constituent units bind along this DNA staircase, eventually forming large complexes (B. Wang, Bhattacharya, et al, 2020) (Figure 1).…”