Programmable protein delivery with a bacterial contractile injection system.
Programmable protein delivery with a bacterial contractile injection system.
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DOI：
10.1038/s41586-023-05870-7
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发表时间：
2023-04
期刊：
影响因子：
64.8
通讯作者：
Zhang, Feng
中科院分区：
文献类型：
--
作者：
Kreitz, Joseph;Friedrich, Mirco J. J.;Guru, Akash;Lash, Blake;Saito, Makoto;Macrae, Rhiannon K. K.;Zhang, Feng
内共生细菌已经进化出复杂的输送系统，使这些生物体能够与宿主生物学相互作用。例如，细胞外收缩注射系统 (eCIS) 是一种类似注射器的大分子复合物，通过驱动刺突穿过细胞膜将蛋白质有效负载注入真核细胞中。最近，人们发现 eCIS 可以靶向小鼠细胞，这提高了利用这些系统进行治疗性蛋白质递送的可能性。然而，eCIS 是否能在人类细胞中发挥作用仍不清楚，而且这些系统识别靶细胞的机制也知之甚少。在这里，我们表明，光杆菌毒力盒（PVC）——一种来自昆虫病原细菌非共生光杆菌的 eCIS——的靶标选择是通过 PVC 尾纤维的远端结合元件对靶标受体的特异性识别来介导的。此外，利用尾部纤维的计算机结构引导工程，我们表明 PVC 可以重新编程以瞄准这些系统本身不瞄准的生物体（包括人类细胞和小鼠），效率接近 100%。最后，我们证明 PVC 可以加载多种蛋白质有效负载，包括 Cas9、碱基编辑器和毒素，并可以功能性地将它们递送到人体细胞中。我们的结果表明，PVC 是一种可编程的蛋白质输送装置，可应用于基因治疗、癌症治疗和生物控制。来自 Photorhabdus asymbiotica 的细胞外收缩注射系统 (eCIS) 的尾部纤维可识别真核宿主细胞上表达的靶标，并且可以重新编程以针对特定的生物体和细胞类型，以递送新型蛋白质有效负载。
Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One example, the extracellular contractile injection systems (eCISs), are syringe-like macromolecular complexes that inject protein payloads into eukaryotic cells by driving a spike through the cellular membrane. Recently, eCISs have been found to target mouse cells, raising the possibility that these systems could be harnessed for therapeutic protein delivery. However, whether eCISs can function in human cells remains unknown, and the mechanism by which these systems recognize target cells is poorly understood. Here we show that target selection by the Photorhabdus virulence cassette (PVC)—an eCIS from the entomopathogenic bacterium Photorhabdus asymbiotica—is mediated by specific recognition of a target receptor by a distal binding element of the PVC tail fibre. Furthermore, using in silico structure-guided engineering of the tail fibre, we show that PVCs can be reprogrammed to target organisms not natively targeted by these systems—including human cells and mice—with efficiencies approaching 100%. Finally, we show that PVCs can load diverse protein payloads, including Cas9, base editors and toxins, and can functionally deliver them into human cells. Our results demonstrate that PVCs are programmable protein delivery devices with possible applications in gene therapy, cancer therapy and biocontrol. The tail fibre of an extracellular contractile injection system (eCIS) from Photorhabdus asymbiotica recognizes targets expressed on eukaryotic host cells, and can be reprogrammed to target specific organisms and cell types for delivery of novel protein payloads.
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影响因子：
3.7
作者：
Green ER;Mecsas J
通讯作者：
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影响因子：
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Hassabis D
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影响因子：
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影响因子：
64.8
作者：
Ge P;Scholl D;Prokhorov NS;Avaylon J;Shneider MM;Browning C;Buth SA;Plattner M;Chakraborty U;Ding K;Leiman PG;Miller JF;Zhou ZH
通讯作者：
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影响因子：
64.5
作者：
Jiang, Feng;Li, Ningning;Gao, Ning
通讯作者：
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