Apaf-1-like receptors are evolutionarily conserved DNA sensors that switch the cell fate between apoptosis and inflammation

Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the ‘apoptosome’ after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR) and plant resistance (R) proteins, whether it is directly involved in innate immunity is still largely unknown. Here, we found that Apaf-1-like receptors (ALRs) from lancelets, fruit flies, mice and humans have conserved DNA sensing functionality. Mechanistically, mammalian Apaf-1 recruits receptor-interacting protein 2 (RIP2, also known as RIPK2) via its WD40 repeat domain and promotes RIP2 oligomerization to initiate NF-κB-driven inflammation upon cytoplasmic DNA recognition. Furthermore, DNA binding of Apaf-1 determines cell fate by switching the cellular processes between intrinsic stimuli-activated apoptosis and inflammation. These findings suggest that ALRs are evolutionarily conserved DNA sensors and serve as cell fate checkpoints, which determine whether cells initiate inflammation or undergo apoptosis by distinct ligand binding.

凋亡蛋白酶激活因子1（Apoptotic protease activating factor 1，Apaf-1）传统上被定义为哺乳动物细胞中的支架蛋白，在结合细胞色素c后可组装形成被称为“凋亡小体”的半胱天冬酶激活平台。尽管Apaf-1在结构上与动物NOD样受体（NOD-like receptor，NLR）以及植物抗性（resistance，R）蛋白相似，但其是否直接参与先天免疫仍未完全明确。本研究发现，来自文昌鱼、果蝇、小鼠和人类的Apaf-1样受体（Apaf-1-like receptors，ALRs）具有保守的DNA感知功能。从机制层面来看，哺乳动物Apaf-1可通过其WD40重复结构域招募受体相互作用蛋白2（receptor-interacting protein 2，RIP2，又称RIPK2），并促进RIP2寡聚化，从而在识别胞质DNA后启动核因子κB（NF-κB）介导的炎症反应。此外，Apaf-1的DNA结合活性可通过在内在刺激激活的凋亡与炎症反应之间切换细胞进程，从而决定细胞命运。本研究结果表明，ALRs是进化上保守的DNA感受器，并可作为细胞命运检查点，通过结合不同配体来决定细胞是启动炎症反应还是发生凋亡。