2026年8月19日，德国海德堡欧洲分子生物学实验室Athanasios Typas等科学家在《自然》上发表研究，揭示了T7噬菌体通过其编码的激酶（T7K）对宿主及自身蛋白进行大规模磷酸化，从而广泛瓦解细菌多种防御系统的全新机制。

细菌与噬菌体处于持续的军备竞赛中，分别演化出防御系统和抗防御系统。目前已知的噬菌体编码的抗防御系统均针对特定细菌防御系统的活性。本研究发现T7噬菌体通过蛋白质磷酸化广泛对抗细菌防御的一种机制。其激酶（T7K）——此前被认为仅能重编程少数宿主蛋白的功能——实际上是一种高度混杂的双特异性激酶，在感染期间可磷酸化几乎所有宿主及噬菌体蛋白。其磷酸化的规模远超大肠杆菌中已知的磷酸化位点，无序列基序特异性，且导致全蛋白质组磷酸化密度高于含约500种激酶的哺乳动物细胞。磷酸化位点的化学计量分析显示，T7K的活性由其C端DNA结合结构域介导，对核酸结合底物具有强烈偏好。这种高度化学计量比的磷酸化能够使靶向DNA或含DNA的细菌防御系统失活。

研究人员通过具体的磷酸化事件，阐明了T7K如何削弱含DNA的Retron-Eco9防御系统的机制，其中毒素关键位点的单点磷酸化模拟突变即可废除防御功能。此外，通过对大量大肠杆菌菌株的筛选，研究人员证明了T7K在自然界中具有广泛的抗防御能力，因为受其拮抗的菌株中含有多种不同的细菌防御系统。T7K同源物几乎仅存在于噬菌体中，其高度混杂的激酶活性可能由其催化中心一个发散的DFG样基序所赋予。

附：英文原文

Title: Pervasive phosphorylation by phage T7 kinase disarms bacterial defences

Author: Bartolec, Tara, Mitosch, Karin, Potel, Clment, Corona, Federico, Yang, Alessio Ling Jie, Karcher, Nicolai, Burtscher, Mira Lea, Koumoutsi, Alexandra, Becher, Isabelle, Mller, Lena Sarah, Bobonis, Jacob, Kumar, Manjeet, Galardini, Marco, Typas, Athanasios, Savitski, Mikhail M.

Issue&Volume: 2026-08-19

Abstract: Bacteria and bacteriophages are in a constant arms race to develop defence and anti-defence systems, respectively. Currently known phage-encoded anti-defence systems are specific to the activity of the targeted bacterial defence system. Here we identify a mechanism by which the T7 bacteriophage broadly counteracts bacterial defences using protein phosphorylation. Its kinase (T7K), which has been reported to redirect the function of a few host proteins is actually a hyperpromiscuous dual-specificity kinase that phosphorylates nearly all host and phage proteins during infection. The scale of phosphorylation vastly exceeds known phosphosites in Escherichia coli, has no sequence motif specificity and results in a higher proteome-wide phosphorylation density than mammalian cells with around 500 kinases. Stoichiometry analysis of phosphorylation sites revealed strong bias in T7K activity towards nucleic-acid-binding substrates mediated by its C-terminal DNA-binding domain. This highly stoichiometric phosphorylation enables the deactivation of DNA-targeting or DNA-containing bacterial defence systems. We provide mechanistic insights into how T7K weakens DNA-containing Retron-Eco9 through specific phosphorylation events, with single phosphomimetic mutations in key sites of the toxin abolishing defence. Moreover, by screening a large collection of E. coli strains, we provide evidence of broad anti-defence abilities of T7K in nature, as counteracted strains contain diverse bacterial defence systems. T7K homologues are found almost exclusively in phages, with hyperpromiscuous kinase activity probably being enabled by a divergent DFG-like motif in the catalytic centre.

DOI: 10.1038/s41586-026-10934-5

Source: https://www.nature.com/articles/s41586-026-10934-5