Wein Tanita, Johnson Alex G, Millman Adi, Lange Katharina, Yirmiya Erez, Hadary Romi, Garb Jeremy, Steinruecke Felix, Hill Aidan B, Kranzusch Philip J, Sorek Rotem
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 7610001, Israel.
Department of Microbiology, Harvard Medical School, Boston, Ma, USA.
bioRxiv. 2023 May 29:2023.05.28.542683. doi: 10.1101/2023.05.28.542683.
Caspase recruitment domains (CARDs) and pyrin domains are important facilitators of inflammasome activity and pyroptosis. Upon pathogen recognition by NLR proteins, CARDs recruit and activate caspases, which, in turn, activate gasdermin pore forming proteins to and induce pyroptotic cell death. Here we show that CARD-like domains are present in defense systems that protect bacteria against phage. The bacterial CARD is essential for protease-mediated activation of certain bacterial gasdermins, which promote cell death once phage infection is recognized. We further show that multiple anti-phage defense systems utilize CARD-like domains to activate a variety of cell death effectors. We find that these systems are triggered by a conserved immune evasion protein that phages use to overcome the bacterial defense system RexAB, demonstrating that phage proteins inhibiting one defense system can activate another. We also detect a phage protein with a predicted CARD-like structure that can inhibit the CARD-containing bacterial gasdermin system. Our results suggest that CARD domains represent an ancient component of innate immune systems conserved from bacteria to humans, and that CARD-dependent activation of gasdermins is conserved in organisms across the tree of life.
半胱天冬酶募集结构域（CARDs）和吡啉结构域是炎性小体活性和细胞焦亡的重要促进因子。在NLR蛋白识别病原体后，CARDs募集并激活半胱天冬酶，而半胱天冬酶又会激活形成孔道的gasdermin蛋白，从而诱导细胞焦亡。在此，我们表明类CARD结构域存在于保护细菌抵御噬菌体的防御系统中。细菌CARD对于蛋白酶介导的某些细菌gasdermin的激活至关重要，一旦识别出噬菌体感染，这些gasdermin就会促进细胞死亡。我们进一步表明，多种抗噬菌体防御系统利用类CARD结构域来激活多种细胞死亡效应器。我们发现这些系统是由一种保守的免疫逃避蛋白触发的，噬菌体利用该蛋白来克服细菌防御系统RexAB，这表明抑制一种防御系统的噬菌体蛋白可以激活另一种。我们还检测到一种具有预测类CARD结构的噬菌体蛋白，它可以抑制含CARD的细菌gasdermin系统。我们的结果表明，CARD结构域代表了从细菌到人类保守的先天免疫系统的一个古老组成部分，并且gasdermin的CARD依赖性激活在整个生命树中的生物体中是保守的。
