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

Abstract

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 E.coli (EPEC) effector NleE using proximity-enabled protein crosslinking. We show that ZPR1 assembles via liquid-liquid phase separation (LLPS) invitro and regulates CHOP-mediated UPRER at the transcriptional level. Interestingly, invitro 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 UPRER pathways at the transcription level in a NleE-ZPR1 cascade-dependent manner. Together, our study reveals the mechanism by which EPEC interferes with CHOP-UPRER via regulating ZPR1 to help pathogens escape host defense.