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EspF, an effector protein secreted by the type III secretion system of EHEC, is primarily responsible for the development of inflammatory colitis. Our previous study revealed that EspF interacts with the host Annexin A6 (ANXA6) protein and targets the endoplasmic reticulum (ER). Given the critical effects of ER stress on the host responses of gastroenteritis, we explored the role of EspF\u2013ANXA6 interaction in ER stress. Caco-2 cells were infected with different strains of EHEC and transfected with modified plasmids to establish in vitro research models. Our results revealed that infection with espF-deletion EHEC strains significantly exacerbated ER stress. Specifically, the phosphorylation of eIF2\u03b1 was elevated, and the expression levels of BiP, ATF4, and CHOP were increased by more than 15% compared to those in cells infected with wild-type EHEC strains. Further experiments showed that EspF co-localizes with BiP and down-regulates the PERK pathway. Meanwhile, the EspF\u2013ANXA6 interaction could aggravate the inhibition of the PERK pathway and stimulate calcium influx to disturb ER homeostasis, eventually leading to apoptosis. Our findings suggest that the EspF\u2013ANXA6 interaction could inhibit ER stress through the PERK pathway, which may limit cell-to-cell communication and block the clearance of bacteria in host cells.<\/jats:p>","DOI":"10.3390\/pathogens14050440","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T07:44:58Z","timestamp":1746171898000},"page":"440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Enterohemorrhagic Escherichia coli O157:H7 Infection Inhibits Host Endoplasmic Reticulum Stress in Intestinal Epithelial Cells via the PERK Pathway"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7306-5967","authenticated-orcid":false,"given":"Litai","family":"Xu","sequence":"first","affiliation":[{"name":"BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shenzhen Children\u2019s Hospital, Shenzhen 518000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoguo","family":"Wang","sequence":"additional","affiliation":[{"name":"BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Gao","sequence":"additional","affiliation":[{"name":"BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao","family":"Zhang","sequence":"additional","affiliation":[{"name":"BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8420-4147","authenticated-orcid":false,"given":"Ying","family":"Hua","sequence":"additional","affiliation":[{"name":"BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510000, China"},{"name":"Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengsong","family":"Wan","sequence":"additional","affiliation":[{"name":"BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1056\/NEJM198303243081203","article-title":"Hemorrhagic Colitis Associated with a Rare Escherichia coli Serotype","volume":"308","author":"Riley","year":"1983","journal-title":"N. 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