{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:42:09Z","timestamp":1790286129245,"version":"4.1.0"},"reference-count":29,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2019,8,22]],"date-time":"2019-08-22T00:00:00Z","timestamp":1566432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31672584"],"award-info":[{"award-number":["31672584"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31702310"],"award-info":[{"award-number":["31702310"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2016M602883"],"award-info":[{"award-number":["2016M602883"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key R&amp;D Program of China","award":["2018YFD0500900"],"award-info":[{"award-number":["2018YFD0500900"]}]},{"name":"Natural Science Basic Research Plan in Shaanxi Province of China","award":["2017JQ30100"],"award-info":[{"award-number":["2017JQ30100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The effectors of the type IV secretion system (T4SS) of bacteria play important roles in mediating bacterial intracellular proliferation and manipulating host-related pathway responses to bacterial infection. Brucella Spp. inhibit the apoptosis of host cells to benefit their own intracellular proliferation. However, the underlying mechanisms between T4SS effectors and Brucella-inhibited apoptosis in goat trophoblast cells remain unclear. Here, based on Brucella suis vaccine strain 2, the VceC was deleted by allelic exchange. We show that \u0394VceC was able to infect and proliferate to high titers in goat trophoblast cells (GTCs) and increase C\/EBP-homologous protein (CHOP)-mediated apoptosis. GRP78 expression decreased upon \u0394VceC infection. In addition, we discovered that the inositolrequiring enzyme 1 (IRE1) pathway was inhibited in this process. Changing endoplasmic reticulum (ER) stress affected Brucella intracellular replication in GTCs. The replication of \u0394VceC was more sensitive under the different ERstress conditions in the GTC line after treatment with ER stress inhibitors 4 phenyl butyric acid (4-PBA) or ER stress activator Tm. Together, our findings show that VceC has a protective effect on the intracellular persistence of Brucella infection, and inhibits ER stress-induced apoptosis in the CHOP pathway. The present work provides new insights for understanding the mechanism of VceC in the establishment of chronic Brucella infection.<\/jats:p>","DOI":"10.3390\/ijms20174104","type":"journal-article","created":{"date-parts":[[2019,8,23]],"date-time":"2019-08-23T10:15:07Z","timestamp":1566555307000},"page":"4104","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["VceC Mediated IRE1 Pathway and Inhibited CHOP-induced Apoptosis to Support Brucella Replication in Goat Trophoblast Cells"],"prefix":"10.3390","volume":"20","author":[{"given":"Feijie","family":"Zhi","sequence":"first","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"},{"name":"College of Veterinary Medicine, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Furong","family":"Bai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junmei","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caixia","family":"Xiang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangdong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"},{"name":"College of Veterinary Medicine, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9693-7292","authenticated-orcid":false,"given":"Aihua","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Animal Biotechnology of the Ministry of Agriculture, Northwest A&amp;F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S1473-3099(06)70382-6","article-title":"The new global map of human brucellosis","volume":"6","author":"Pappas","year":"2006","journal-title":"Lancet Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1146\/annurev-animal-021815-111326","article-title":"Brucella spp. Virulence Factors and Immunity","volume":"4","author":"Byndloss","year":"2016","journal-title":"Annu. Rev. Anim. Biosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/0147-9571(93)90001-L","article-title":"Pathogenesis of abortion of bovine brucellosis","volume":"16","author":"Samartino","year":"1993","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1111\/cmi.12452","article-title":"The changing nature of the Brucella-containing vacuole","volume":"17","author":"Celli","year":"2015","journal-title":"Cell. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3389\/fcimb.2016.00030","article-title":"Establishment of Chronic Infection: Brucella\u2019s Stealth Strategy","volume":"6","author":"Ahmed","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.micinf.2017.12.006","article-title":"Alternative strategies for vaccination to brucellosis","volume":"20","author":"Pascual","year":"2018","journal-title":"Microbes Infect."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.meegid.2013.11.011","article-title":"Common antigens prediction in bacterial bioweapons: A perspective for vaccine design","volume":"21","author":"Jaiswal","year":"2014","journal-title":"Infect. Genet. Evol."},{"key":"ref_8","first-page":"5","article-title":"Efficacy of Brucella abortus vaccine strain RB51 compared to the reference vaccine Brucella abortus strain 19 in water buffalo","volume":"46","author":"Caporale","year":"2010","journal-title":"Vet. Ital."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.vaccine.2015.09.116","article-title":"Brucella suis strain 2 vaccine is safe and protective against heterologous Brucella spp. infections","volume":"34","author":"Zhu","year":"2016","journal-title":"Vaccine"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Myeni, S., Child, R., Ng, T.W., Kupko, J.J., Wehrly, T.D., Porcella, S.F., Knodler, L.A., and Celli, J. (2013). Brucella modulates secretory trafficking via multiple type IV secretion effector proteins. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003556"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1111\/j.1365-2958.2008.06487.x","article-title":"Identification of VceA and VceC, two members of the VjbR regulon that are translocated into macrophages by the Brucella type IV secretion system","volume":"70","author":"Sun","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e00418-12","DOI":"10.1128\/mBio.00418-12","article-title":"Sensing of Bacterial Type IV Secretion via the Unfolded Protein Response","volume":"4","author":"Starr","year":"2013","journal-title":"mBio"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/nature17631","article-title":"NOD1 and NOD2 signalling links ER stress with inflammation","volume":"532","author":"Byndloss","year":"2016","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/j.1574-6976.2012.00334.x","article-title":"Internal affairs: Investigating the Brucella intracellular lifestyle","volume":"36","author":"Gorvel","year":"2012","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1084\/jem.20030088","article-title":"Brucella evades macrophage killing via VirB-dependent sustained interactions with the endoplasmic reticulum","volume":"198","author":"Celli","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Smith, J.A., Khan, M., Magnani, D.D., Harms, J.S., Durward, M., Radhakrishnan, G.K., Liu, Y.P., and Splitter, G.A. (2013). Brucella induces an unfolded protein response via TcpB that supports intracellular replication in macrophages. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003785"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fcimb.2016.00019","article-title":"Brucella suis Vaccine Strain 2 Induces Endoplasmic Reticulum Stress that Affects Intracellular Replication in Goat Trophoblast Cells In vitro","volume":"6","author":"Wang","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R622-6","DOI":"10.1016\/j.cub.2012.07.004","article-title":"Unfolded protein response","volume":"22","author":"Cao","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"735","DOI":"10.2174\/1566524015666150921105453","article-title":"ER stress and autophagy","volume":"15","author":"Lee","year":"2015","journal-title":"Curr. Mol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/sj.embor.7400779","article-title":"Mediators of endoplasmic reticulum stress-induced apoptosis","volume":"7","author":"Szegezdi","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1146\/annurev-micro-090110-102905","article-title":"Interactions of the human pathogenic Brucella species with their hosts","volume":"65","author":"Atluri","year":"2011","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1128\/IAI.68.1.342-351.2000","article-title":"In vitro Brucella suis infection prevents the programmed cell death of human monocytic cells","volume":"68","author":"Gross","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1086\/375223","article-title":"Monocyte and lymphocyte apoptosis resistance in acute and chronic brucellosis and its possible implications in clinical management","volume":"36","author":"Tolomeo","year":"2003","journal-title":"Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1099\/mic.0.030619-0","article-title":"Cytotoxicity of Brucella smooth strains for macrophages is mediated by increased secretion of the type IV secretion system","volume":"155","author":"Zhong","year":"2009","journal-title":"Microbiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/s41467-017-00171-w","article-title":"A non-canonical pathway regulates ER stress signaling and blocks ER stress-induced apoptosis and heart failure","volume":"8","author":"Yao","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1016\/j.molimm.2009.12.003","article-title":"CHOP-independent apoptosis and pathway-selective induction of the UPR in developing plasma cells","volume":"47","author":"Masciarelli","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/ni.1857","article-title":"TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages","volume":"11","author":"Martinon","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Taguchi, Y., Imaoka, K., Kataoka, M., Uda, A., Nakatsu, D., Horii-Okazaki, S., Kunishige, R., Kano, F., and Murata, M. (2015). Yip1A, a novel host factor for the activation of the IRE1 pathway of the unfolded protein response during Brucella infection. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004747"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5184","DOI":"10.18632\/oncotarget.23706","article-title":"Brucella induces unfolded protein response and inflammatory response via GntR in alveolar macrophages","volume":"9","author":"Zhou","year":"2018","journal-title":"Oncotarget"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/17\/4104\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:13:11Z","timestamp":1760188391000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/17\/4104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,22]]},"references-count":29,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ijms20174104"],"URL":"https:\/\/doi.org\/10.3390\/ijms20174104","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,22]]}}}