How pathogens manipulate host UPR^ER to mediate immune evasion is largely unknown. Here, we identify the host zinc finger protein ZPR1 as an interacting partner of the enteropathogenic E. coli (EPEC) effector NleE using proximity-enabled protein crosslinking. We show that ZPR1 assembles via liquid-liquid phase separation (LLPS) in vitro and regulates CHOP-mediated UPR^ER at the transcriptional level. Interestingly, in vitro studies show that the ZPR1 binding ability with K63-ubiquitin chains, which promotes LLPS of ZPR1, is disrupted by NleE. Further analyses indicate that EPEC restricts host UPR^ER pathways at the transcription level in a NleE-ZPR1 cascade-dependent manner. Together, our study reveals the mechanism by which EPEC interferes with CHOP-UPR^ER via regulating ZPR1 to help pathogens escape host defense.

病原体如何操纵宿主 UPR ^ER介导免疫逃避尚不清楚。在这里，我们使用邻近蛋白交联将宿主锌指蛋白 ZPR1 识别为致病性大肠杆菌(EPEC) 效应子 NleE 的相互作用伙伴。我们发现 ZPR1在体外通过液-液相分离 (LLPS) 进行组装，并在转录水平上调节 CHOP 介导的 UPR ^{ER 。}有趣的是，体外研究表明，NleE 破坏了 ZPR1 与 K63 泛素链的结合能力，从而促进 ZPR1 的 LLPS。进一步的分析表明，EPEC以 NleE-ZPR1 级联依赖性方式在转录水平限制宿主 UPR ^ER通路。总之，我们的研究揭示了 EPEC通过调节 ZPR1干扰 CHOP-UPR ^ER以帮助病原体逃避宿主防御的机制。