近日，以色列魏茨曼科学研究所教授Rotem Sorek及其课题组实现结构引导下抑制宿主免疫的病毒蛋白发现。2025年1月23日，《细胞》杂志在线发表了这项成果。
研究人员开发了一种系统筛选病毒编码蛋白的方法，以寻找能够与宿主免疫蛋白物理结合的抑制剂。研究人员重点研究了Thoeris和CBASS，它们是细菌防御系统，是真核生物Toll/白介素-1受体（TIR）和环磷酸鸟苷-腺苷酸合酶（cGAS）免疫的祖先。研究人员发现了七个家族的Thoeris和CBASS抑制剂，涵盖了在噬菌体中广泛分布的数千个基因。已验证的抑制剂与相应免疫蛋白对等体有广泛的物理相互作用，所有抑制剂都能阻断免疫蛋白的活性位点。
值得注意的是，某些噬菌体编码的细菌TIR蛋白抑制剂能够与远缘的人的植物免疫TIR蛋白结合并抑制它们，而某些噬菌体衍生的细菌cGAS类酶抑制剂能够抑制人类cGAS。这些结果表明，噬菌体是一个储存免疫调节蛋白的宝库，这些蛋白能够抑制细菌、动物和植物的免疫反应。
据介绍，病毒编码能够抑制宿主防御的蛋白质，但迄今为止，从数百万个现有病毒序列中筛选免疫调节蛋白仍然不切实际。
附：英文原文
Title: Structure-guided discovery of viral proteins that inhibit host immunity
Author: Erez Yirmiya, Samuel J. Hobbs, Azita Leavitt, Ilya Osterman, Carmel Avraham, Dina Hochhauser, Barak Madhala, Marharyta Skovorodka, Joel M.J. Tan, Hunter C. Toyoda, Igor Chebotar, Maxim Itkin, Sergey Malitsky, Gil Amitai, Philip J. Kranzusch, Rotem Sorek
Issue&Volume: 2025-01-23
Abstract: Viruses encode proteins that inhibit host defenses, but sifting through the millions of available viral sequences for immune-modulatory proteins has been so far impractical. Here, we develop a process to systematically screen virus-encoded proteins for inhibitors that physically bind host immune proteins. Focusing on Thoeris and CBASS, bacterial defense systems that are the ancestors of eukaryotic Toll/interleukin-1 receptor (TIR) and cyclic GMP-AMP synthase (cGAS) immunity, we discover seven families of Thoeris and CBASS inhibitors, encompassing thousands of genes widespread in phages. Verified inhibitors exhibit extensive physical interactions with the respective immune protein counterpart, with all inhibitors blocking the active site of the immune protein. Remarkably, a phage-encoded inhibitor of bacterial TIR proteins can bind and inhibit distantly related human and plant immune TIRs, and a phage-derived inhibitor of bacterial cGAS-like enzymes can inhibit the human cGAS. Our results demonstrate that phages are a reservoir for immune-modulatory proteins capable of inhibiting bacterial, animal, and plant immunity.
DOI: 10.1016/j.cell.2024.12.035
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01478-8