Kibby Emily M, Robbins Laurel K, Deep Amar, Min Nathan K, Whalen Lindsay A, Nagy Toni A, Freeborn Layla, Corbett Kevin D, Whiteley Aaron T
Department of Biochemistry, University of Colorado Boulder, Boulder, CO, USA.
Interdisciplinary Quantitative Biology Program (IQ Biology), BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA.
bioRxiv. 2024 Dec 17:2024.12.17.629029. doi: 10.1101/2024.12.17.629029.
Immune systems must rapidly sense viral infections to initiate antiviral signaling and protect the host. Bacteria encode >100 distinct viral (phage) defense systems and each has evolved to sense crucial components or activities associated with the viral lifecycle. Here we used a high-throughput AlphaFold-multimer screen to discover that a bacterial NLR-related protein directly senses multiple phage proteins, thereby limiting immune evasion. Phages encoded as many as 5 unrelated activators that were predicted to bind the same interface of a C-terminal sensor domain. Genetic and biochemical assays confirmed activators bound to the bacterial NLR-related protein at high affinity, induced oligomerization, and initiated signaling. This work highlights how strategies can identify complex protein interaction networks that regulate immune signaling across the tree of life.
免疫系统必须迅速感知病毒感染，以启动抗病毒信号传导并保护宿主。细菌编码超过100种不同的病毒（噬菌体）防御系统，并且每种系统都经过进化以感知与病毒生命周期相关的关键成分或活动。在这里，我们使用高通量AlphaFold多聚体筛选发现，一种细菌NLR相关蛋白可直接感知多种噬菌体蛋白，从而限制免疫逃逸。噬菌体编码多达5种不相关的激活剂，预计这些激活剂会结合C端传感器结构域的同一界面。遗传和生化分析证实，激活剂以高亲和力与细菌NLR相关蛋白结合，诱导寡聚化并启动信号传导。这项工作突出了策略如何能够识别调节整个生命树免疫信号传导的复杂蛋白质相互作用网络。
