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Here, we show that Pic, a class 2 SPATE protein produced by<jats:italic>Shigella flexneri<\/jats:italic>2a, uropathogenic and enteroaggregative<jats:italic>Escherichia coli<\/jats:italic>strains, targets a broad range of human leukocyte adhesion proteins. Substrate specificity was restricted to glycoproteins rich in O-linked glycans, including CD43, CD44, CD45, CD93, CD162 (PSGL-1; P-selectin glycoprotein ligand 1), and the surface-attached chemokine fractalkine, all implicated in leukocyte trafficking, migration, and inflammation. N-terminal sequencing of proteolytic products revealed Pic (protease involved in colonization) cleavage sites to occur before Thr or Ser residues. The purified carbohydrate sLewis-X implied in inflammation and malignancy inhibited cleavage of PSGL-1 by Pic. Exposure of human leukocytes to purified Pic resulted in polymorphonuclear cell activation, but impaired chemotaxis and transmigration; Pic-treated T cells underwent programmed cell death. We also show that the Pic-related protease Tsh\/Hbp, implicated in extraintestinal infections, exhibited a spectrum of substrates similar to those cleaved by Pic. In the guinea pig keratoconjunctivitis model, a<jats:italic>Shigella pic<\/jats:italic>mutant induced greater inflammation than its parent strain. We suggest that the class-2 SPATEs represent unique immune-modulating bacterial virulence factors.<\/jats:p>","DOI":"10.1073\/pnas.1101006108","type":"journal-article","created":{"date-parts":[[2011,7,19]],"date-time":"2011-07-19T03:35:45Z","timestamp":1311046545000},"page":"12881-12886","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":99,"title":["Serine protease autotransporters from<i>Shigella flexneri<\/i>and pathogenic<i>Escherichia coli<\/i>target a broad range of leukocyte glycoproteins"],"prefix":"10.1073","volume":"108","author":[{"given":"Fernando","family":"Ruiz-Perez","sequence":"first","affiliation":[{"name":"Center for Vaccine Development and"},{"name":"Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA 22908"}]},{"given":"Rezwanul","family":"Wahid","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"}]},{"given":"Christina S.","family":"Faherty","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"}]},{"given":"Krishnan","family":"Kolappaswamy","sequence":"additional","affiliation":[{"name":"Program of Comparative Medicine, Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201; and"}]},{"given":"Liliana","family":"Rodriguez","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"}]},{"given":"Araceli","family":"Santiago","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"},{"name":"Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA 22908"}]},{"given":"Ebony","family":"Murphy","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"}]},{"given":"Alan","family":"Cross","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"}]},{"given":"Marcelo B.","family":"Sztein","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"}]},{"given":"James P.","family":"Nataro","sequence":"additional","affiliation":[{"name":"Center for Vaccine Development and"},{"name":"Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA 22908"}]}],"member":"341","published-online":{"date-parts":[[2011,7,18]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro818"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1053\/j.spid.2005.12.008"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(98)01318-3"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.3.1231-1243.2001"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.12.7105-7113.2002"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0008223"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.2003.03492.x"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.2.1053-1060.2001"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.6.1091"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.62.4.1369-1380.1994"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.11.5587-5596.1999"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1097(03)00862-0"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.65.11.4606-4614.1997"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.71.11.6307-6319.2003"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01494-08"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00523-10"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.01542-06"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.43.8.4076-4082.2005"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.08.019"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2417"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830231110"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209581"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V86.2.502.bloodjournal862502"},{"key":"e_1_3_3_24_2","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.4049\/jimmunol.158.6.2543","article-title":"Apoptosis of immature thymocytes mediated by E2\/CD99","volume":"158","author":"Bernard G","year":"1997","unstructured":"G Bernard, et al., Apoptosis of immature thymocytes mediated by E2\/CD99. 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