Bacterial effector restricts liquid-liquid phase separation of ZPR1 to antagonize host UPRER

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

Automated summary

In this study, the host protein ZPR1 was identified as an interacting partner of the EPEC effector NleE through protein crosslinking. It was found that ZPR1 regulates CHOP-mediated UPRER at the transcriptional level through liquid-liquid phase separation. Interestingly, NleE disrupts the binding ability of ZPR1 with K63-ubiquitin chains, which promotes its liquid-liquid phase separation. Further analysis showed that EPEC restricts host UPRER pathways at the transcription level in a cascade-dependent manner between NleE and ZPR1. Overall, this study reveals the mechanism by which EPEC interferes with CHOP-UPRER through regulating ZPR1 to facilitate immune evasion.