{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:34:40Z","timestamp":1792010080818,"version":"4.4.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:00:00Z","timestamp":1670371200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31730094"],"award-info":[{"award-number":["31730094"]}],"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":["32072821"],"award-info":[{"award-number":["32072821"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the fifth phase of the \u201c333 Project\u201d scientific research project in Jiangsu Province","award":["BRA2020002"],"award-info":[{"award-number":["BRA2020002"]}]},{"name":"The Priority Academic Program Development of Jiangsu Higher Education Institutions","award":["PAPD"],"award-info":[{"award-number":["PAPD"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>Invasion plasmid antigen J (IpaJ) is a protein with cysteine protease activity that is present in <jats:italic>Salmonella<\/jats:italic> and <jats:italic>Shigella<\/jats:italic> species. <jats:italic>Salmonella enterica<\/jats:italic> serovar Pullorum uses IpaJ to inhibit the NF-\u03baB pathway and the subsequent inflammatory response, resulting in bacterial survival in host macrophages. In the present study, we performed a DNA pull-down assay and EMSA and identified ItrA, a new DeoR family transcriptional regulator that could control the expression of IpaJ by directly binding to the promoter of <jats:italic>ipaJ<\/jats:italic>. The deletion of <jats:italic>itrA<\/jats:italic> inhibited the transcription of <jats:italic>ipaJ<\/jats:italic> in <jats:italic>Salmonella<\/jats:italic>. Tn-Seq revealed that two regulators of <jats:italic>Salmonella<\/jats:italic> pathogenicity island 1 (SPI-1), namely HilA and HilD, regulated the secretion of IpaJ. The deletion of <jats:italic>hilA<\/jats:italic>, <jats:italic>hilD<\/jats:italic> or SPI-1 inhibited the secretion of IpaJ in both cultured medium and <jats:italic>Salmonella<\/jats:italic>-infected cells. In contrast, the strain with the deletion of <jats:italic>ssrB<\/jats:italic> (an SPI-2 regulator-encoding gene) displayed normal IpaJ secretion, indicating that IpaJ is an effector of the SPI-1-encoded type III secretion system (T3SS1). To further demonstrate the role of IpaJ in host cells, we performed quantitative phosphoproteomics and compared the fold changes in signaling molecules in HeLa cells infected with wild-type <jats:italic>S<\/jats:italic>. Pullorum C79-13 with those in HeLa cells infected with the <jats:italic>ipaJ<\/jats:italic>-deleted strain C79-13\u0394pSPI12. Both phosphoproteomics and Western blot analyses revealed that p-MEK and p-ERK molecules were increased in C79-13\u0394pSPI12- and C79-13\u0394pSPI12-p<jats:italic>ipaJ<\/jats:italic>(C45A)-infected cells; and Co-IP assays demonstrated that IpaJ interacts with Ras to reduce its ubiquitination, indicating that IpaJ can inhibit the activation of the MAPK signaling pathway.<\/jats:p>","DOI":"10.1371\/journal.ppat.1011005","type":"journal-article","created":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T18:30:21Z","timestamp":1670437821000},"page":"e1011005","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["The Salmonella T3SS1 effector IpaJ is regulated by ItrA and inhibits the MAPK signaling pathway"],"prefix":"10.1371","volume":"18","author":[{"given":"Chao","family":"Yin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaojie","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyun","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinan","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0923-9758","authenticated-orcid":true,"given":"Qiuchun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,12,7]]},"reference":[{"issue":"15","key":"ppat.1011005.ref001","doi-asserted-by":"crossref","first-page":"4148","DOI":"10.1128\/JB.184.15.4148-4160.2002","article-title":"DNA-binding activities of the HilC and HilD virulence regulatory proteins of Salmonella enterica serovar Typhimurium","volume":"184","author":"IN Olekhnovich","year":"2002","journal-title":"J Bacteriol"},{"issue":"3","key":"ppat.1011005.ref002","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3390\/microorganisms8030407","article-title":"Salmonella virulence and immune escape","volume":"8","author":"M Wang","year":"2020","journal-title":"Microorganisms"},{"issue":"38","key":"ppat.1011005.ref003","doi-asserted-by":"crossref","first-page":"14591","DOI":"10.1073\/pnas.0801205105","article-title":"HilD-mediated transcriptional cross-talk between SPI-1 and SPI-2","volume":"105","author":"VH Bustamante","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"7","key":"ppat.1011005.ref004","doi-asserted-by":"crossref","first-page":"e1006497","DOI":"10.1371\/journal.ppat.1006497","article-title":"The transcriptional regulator SsrB is involved in a molecular switch controlling virulence lifestyles of Salmonella","volume":"13","author":"D P\u00e9rez-Morales","year":"2017","journal-title":"PLoS Pathog"},{"issue":"1\u20132","key":"ppat.1011005.ref005","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1002\/prca.201100083","article-title":"The current Salmonella-host interactome","volume":"6","author":"S Schleker","year":"2012","journal-title":"Proteomics Clin Appl"},{"issue":"4","key":"ppat.1011005.ref006","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.tim.2018.01.010","article-title":"Host cell targeting by enteropathogenic bacteria T3SS effectors","volume":"26","author":"L Pinaud","year":"2018","journal-title":"Trends Microbiol"},{"issue":"4","key":"ppat.1011005.ref007","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1128\/IAI.01250-09","article-title":"Bacterial guanine nucleotide exchange factors SopE-like and WxxxE effectors","volume":"78","author":"R Bulgin","year":"2010","journal-title":"Infect Immun"},{"key":"ppat.1011005.ref008","doi-asserted-by":"crossref","first-page":"16025","DOI":"10.1038\/nmicrobiol.2016.25","article-title":"Intermediate filaments enable pathogen docking to trigger type 3 effector translocation","volume":"1","author":"BC Russo","year":"2016","journal-title":"Nat Microbiol"},{"issue":"12","key":"ppat.1011005.ref009","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1046\/j.1462-5822.2001.00158.x","article-title":"Role of tyrosine kinases and the tyrosine phosphatase SptP in the interaction of Salmonella with host cells","volume":"3","author":"S Murli","year":"2001","journal-title":"Cell Microbiol"},{"issue":"4","key":"ppat.1011005.ref010","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.chom.2008.02.016","article-title":"Salmonella AvrA coordinates suppression of host immune and apoptotic defenses via JNK pathway blockade","volume":"3","author":"RM Jones","year":"2008","journal-title":"Cell Host Microbe"},{"issue":"17","key":"ppat.1011005.ref011","doi-asserted-by":"crossref","first-page":"6063","DOI":"10.3390\/ijms21176063","article-title":"AvrA exerts inhibition of NF-\u03baB pathway in its na\u00efve Salmonella serotype through suppression of p-JNK and Beclin-1 molecules","volume":"21","author":"C Yin","year":"2020","journal-title":"Int J Mol Sci"},{"key":"ppat.1011005.ref012","doi-asserted-by":"crossref","first-page":"686","DOI":"10.3389\/fimmu.2020.00686","article-title":"Salmonella Enteritidis effector AvrA suppresses autophagy by reducing Beclin-1 protein","volume":"11","author":"Y Jiao","year":"2020","journal-title":"Front Immunol"},{"issue":"7443","key":"ppat.1011005.ref013","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/nature12004","article-title":"Proteolytic elimination of N-myristoyl modifications by the Shigella virulence factor IpaJ","volume":"496","author":"N Burnaevskiy","year":"2013","journal-title":"Nature"},{"issue":"9","key":"ppat.1011005.ref014","doi-asserted-by":"crossref","first-page":"898","DOI":"10.4014\/jmb.0812.694","article-title":"Identification of Salmonella pullorum genomic sequences using suppression subtractive hybridization","volume":"19","author":"L Qiuchun","year":"2009","journal-title":"J Microbiol Biotechnol"},{"issue":"4","key":"ppat.1011005.ref015","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1080\/03079457.2018.1471195","article-title":"Construction of pSPI12-cured Salmonella enterica serovar Pullorum and identification of IpaJ as an immune response modulator","volume":"47","author":"C Yin","year":"2018","journal-title":"Avian Pathol"},{"issue":"3","key":"ppat.1011005.ref016","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1080\/03079457.2017.1412084","article-title":"A rapid method to identify Salmonella enterica serovar Gallinarum biovar Pullorum using a specific target gene ipaJ","volume":"47","author":"L Xu","year":"2018","journal-title":"Avian Pathol"},{"issue":"3","key":"ppat.1011005.ref017","first-page":"e00875","article-title":"The invasion plasmid antigen J (IpaJ) from Salmonella inhibits NF-\u03baB activation by suppressing I\u03baB\u03b1 ubiquitination","volume":"88","author":"Q Li","year":"2020","journal-title":"Infect Immun"},{"issue":"3","key":"ppat.1011005.ref018","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1046\/j.1365-2958.2003.03322.x","article-title":"AraC\/XylS family members, HilD and HilC, directly activate virulence gene expression independently of HilA in Salmonella typhimurium","volume":"47","author":"S Akbar","year":"2003","journal-title":"Mol Microbiol"},{"issue":"1","key":"ppat.1011005.ref019","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1080\/21505594.2017.1392428","article-title":"Identification of a novel gene in ROD9 island of Salmonella Enteritidis involved in the alteration of virulence-associated genes expression","volume":"9","author":"S Das","year":"2018","journal-title":"Virulence"},{"key":"ppat.1011005.ref020","doi-asserted-by":"crossref","first-page":"127085","DOI":"10.1016\/j.micres.2022.127085","article-title":"Identification of two Sel1-like proteins in SPI-19 of Salmonella enterica serovar Pullorum that can mediate bacterial infection through T3SS","volume":"262","author":"Y Zhang","year":"2022","journal-title":"Microbiol Res"},{"issue":"24","key":"ppat.1011005.ref021","doi-asserted-by":"crossref","first-page":"7916","DOI":"10.1128\/AEM.02843-13","article-title":"SdrA, a new DeoR family regulator involved in Streptomyces avermitilis morphological development and antibiotic production","volume":"79","author":"D Ulanova","year":"2013","journal-title":"Appl Environ Microbiol"},{"issue":"6","key":"ppat.1011005.ref022","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1111\/j.1365-2958.2007.05754.x","article-title":"Identification of a transcriptional regulator that controls intracellular gene expression in Salmonella Typhi","volume":"64","author":"E Haghjoo","year":"2007","journal-title":"Mol Microbiol"},{"issue":"18","key":"ppat.1011005.ref023","doi-asserted-by":"crossref","first-page":"4280","DOI":"10.1111\/febs.12856","article-title":"Structure of the effector-binding domain of deoxyribonucleoside regulator DeoR from Bacillus subtilis","volume":"281","author":"J \u0160kerlov\u00e1","year":"2014","journal-title":"FEBS J"},{"issue":"4","key":"ppat.1011005.ref024","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1111\/j.1365-2958.2008.06318.x","article-title":"Crystal structures of the effector-binding domain of repressor central glycolytic gene regulator from Bacillus subtilis reveal ligand-induced structural changes upon binding of several glycolytic intermediates","volume":"69","author":"P Rez\u00e1cov\u00e1","year":"2008","journal-title":"Mol Microbiol"},{"issue":"3","key":"ppat.1011005.ref025","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1094\/MPMI-10-19-0290-R","article-title":"A DeoR-type transcription regulator is required for sugar-induced expression of type III secretion-encoding genes in Pseudomonas syringae pv. tomato DC3000","volume":"33","author":"SE Turner","year":"2020","journal-title":"Mol Plant Microbe Interact"},{"issue":"1","key":"ppat.1011005.ref026","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/j.1460-2075.1989.tb03380.x","article-title":"Purification and characterization of the deoR repressor of Escherichia coli","volume":"8","author":"L Mortensen","year":"1989","journal-title":"EMBO J"},{"issue":"21","key":"ppat.1011005.ref027","doi-asserted-by":"crossref","first-page":"6241","DOI":"10.1128\/JB.185.21.6241-6254.2003","article-title":"Involvement of an inducible fructose phosphotransferase operon in Streptococcus gordonii biofilm formation","volume":"185","author":"CY Loo","year":"2003","journal-title":"J Bacteriol"},{"issue":"3","key":"ppat.1011005.ref028","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.tim.2020.09.012","article-title":"Host Delipidation mediated by bacterial effectors","volume":"29","author":"L Mei","year":"2021","journal-title":"Trends Microbiol"},{"issue":"1","key":"ppat.1011005.ref029","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.molcel.2015.01.040","article-title":"Myristoylome profiling reveals a concerted mechanism of ARF GTPase deacylation by the bacterial protease IpaJ","volume":"58","author":"N Burnaevskiy","year":"2015","journal-title":"Mol Cell"},{"issue":"16","key":"ppat.1011005.ref030","doi-asserted-by":"crossref","first-page":"8754","DOI":"10.1073\/pnas.97.16.8754","article-title":"Striking a balance: Modulation of the actin cytoskeleton by Salmonella","volume":"97","author":"JE Galan","year":"2000","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1011005.ref031","first-page":"348","article-title":"High-resolution genetic analysis of the requirements for horizontal transmission of the ESBL plasmid from Escherichia coli O104:H4","author":"Y Yoshiharu","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"ppat.1011005.ref032","doi-asserted-by":"crossref","first-page":"386","DOI":"10.3389\/fvets.2019.00386","article-title":"Application of monoclonal antibodies developed against the IpaJ protein for detection of chickens infected with Salmonella enterica serovar Pullorum using competitive ELISA","volume":"6","author":"K Yin","year":"2019","journal-title":"Front Vet Sci"}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011005","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T18:30:48Z","timestamp":1670437848000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1011005"}},"subtitle":[],"editor":[{"given":"William","family":"Navarre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,12,7]]},"references-count":32,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,12,7]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1011005","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,7]]}}}