Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Nucleic Acids Res. 2023 Apr 11;51(6):2574-2585. doi: 10.1093/nar/gkad090.
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.
在感知到细胞质和/或病毒双链 (ds)DNA 后，缺失黑色素瘤 2 (AIM2) 样受体 (ALR) 会组装成丝状信号平台，从而引发炎症反应。ALR 在宿主先天防御中的多功能且关键作用正日益受到重视；然而，AIM2 及其相关 IFI16 如何特异性识别 dsDNA 而不是其他核酸的机制仍知之甚少（即单链 (ss)DNA、dsRNA、ssRNA 和 DNA:RNA 杂交）。在这里，我们发现尽管 AIM2 可以与各种核酸相互作用，但它优先结合并组装成纤维，且这种结合和组装在双链 DNA 中具有双链长度依赖性。此外，AIM2 寡聚物在除 dsDNA 以外的核酸上组装不仅显示出较少有序的丝状结构，而且无法诱导下游 ASC 的聚合。同样，虽然 IFI16 比 AIM2 具有更广泛的核酸选择性，但它也以双链长度依赖性的方式优先结合并最容易在 dsDNA 上寡聚化。然而，IFI16 不会在单链核酸上形成纤维，也不会加速 ASC 的聚合，无论结合的核酸如何。总之，我们揭示了纤维组装是 ALR 区分核酸的重要组成部分。
