{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T02:58:09Z","timestamp":1781665089676,"version":"3.54.5"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"36","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,9,8]]},"abstract":"<jats:p>\n                    Signal peptides of membrane proteins are cleaved by endoplasmic reticulum-resident signal peptidase, and thus, are not present on mature membrane proteins. Here, we report that, contrary to the paradigm, the signal peptide of ruminant CD18, the \u03b2-subunit of \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    -integrins, is not cleaved. Intriguingly, the intact signal peptide of CD18 is responsible for the susceptibility of ruminant leukocytes to\n                    <jats:italic>Mannheimia<\/jats:italic>\n                    (\n                    <jats:italic>Pasteurella<\/jats:italic>\n                    )\n                    <jats:italic>haemolytica<\/jats:italic>\n                    leukotoxin (Lkt). Inhibition of Lkt-induced cytolysis of ruminant leukocytes by CD18 peptide analogs revealed that the Lkt-binding site is formed by amino acids 5\u201317 of CD18, which, surprisingly, comprise most of the signal sequence. Flow cytometric analysis of ruminant leukocytes indicated the presence of the signal peptide on mature CD18 molecules expressed on the cell surface. Analysis of transfectants expressing CD18 containing the FLAG epitope at the putative cleavage site confirmed that the signal peptide of bovine CD18 is not cleaved. Analysis of the signal sequence of CD18 of eight ruminants and five nonruminants revealed that the signal sequence of CD18 of ruminants contains \u201ccleavage-inhibiting\u201d Q, whereas that of nonruminants contains \u201ccleavage-conducive\u201d G at position \u22125 relative to the cleavage site. Site-directed mutagenesis of Q to G at position \u22125 of the signal peptide of bovine CD18 resulted in the cleavage of the signal peptide and abrogation of cytolysis of transfectants expressing bovine CD18 carrying the Q(\u22125)G mutation. We propose that engineering cattle and other ruminants to contain this mutation would provide a novel technology to render them less susceptible to pneumonic pasteurellosis and concomitant economic losses.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0906775106","type":"journal-article","created":{"date-parts":[[2009,8,24]],"date-time":"2009-08-24T22:06:24Z","timestamp":1251151584000},"page":"15448-15453","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Intact signal peptide of CD18, the \u03b2-subunit of \u03b2\n                    <sub>2<\/sub>\n                    -integrins, renders ruminants susceptible to\n                    <i>Mannheimia haemolytica<\/i>\n                    leukotoxin"],"prefix":"10.1073","volume":"106","author":[{"given":"Sudarvili","family":"Shanthalingam","sequence":"first","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7040"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subramaniam","family":"Srikumaran","sequence":"additional","affiliation":[{"name":"Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, WA 99164-7040"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,9,8]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.67.3.835"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01868635"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2005.07.013"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0749-0720(15)30310-8"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-4579(00)01262-4"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/9780470344880.ch20"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1051\/vetres:2004044"},{"key":"e_1_3_3_8_2","first-page":"33","article-title":"Bovine respiratory disease: Commercial vaccines currently available in Canada","volume":"41","author":"Bowland SL","year":"2000","unstructured":"SL Bowland, PE Shewn, Bovine respiratory disease: Commercial vaccines currently available in Canada. Can Vet J 41, 33\u201348 (2000).","journal-title":"Can Vet J"},{"key":"e_1_3_3_9_2","first-page":"197","volume-title":"Pasturella and Pasteurellosis","author":"Frank GH","year":"1989","unstructured":"GH Frank, Pasteurellosis of cattle. Pasturella and Pasteurellosis, eds C Adlam, JM Rutter (Academic, New York), pp. 197\u2013222 (1989)."},{"key":"e_1_3_3_10_2","first-page":"1","article-title":"A review of the lesions in shipping fever of cattle","volume":"22","author":"Rehmtulla AJ","year":"1981","unstructured":"AJ Rehmtulla, RG Thomson, A review of the lesions in shipping fever of cattle. Can Vet J 22, 1\u20138 (1981).","journal-title":"Can Vet J"},{"key":"e_1_3_3_11_2","first-page":"S48","article-title":"Molecular aspects of virulence of Pasteurella haemolytica","volume":"54","author":"Confer AW","year":"1990","unstructured":"AW Confer, RJ Panciera, KD Clinkenbeard, DA Moiser, Molecular aspects of virulence of Pasteurella haemolytica. Can J Vet Res 54, S48\u2013S52 (1990).","journal-title":"Can J Vet Res"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.63.3.1033-1039.1995"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1006\/mpat.1997.0181"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.7.3916-3922.2000"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vetmic.2008.07.015"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.171.2.916-928.1989"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.57.10.3210-3213.1989"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.57.5.1465-1469.1989"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.30.2.615-616.1980"},{"key":"e_1_3_3_20_2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2460\/ajvr.1986.47.01.67","article-title":"Pasteurella haemolytica leukotoxin: Chemiluminescent responses of peripheral blood leukocytes from several different mammalian species to leukotoxin- and opsonin-treated living and killed Pasteurella haemolytica and Staphylococcus aureus","volume":"47","author":"Chang YF","year":"1986","unstructured":"YF Chang, HW Renshaw, RJ Martens, CW Livingston, Pasteurella haemolytica leukotoxin: Chemiluminescent responses of peripheral blood leukocytes from several different mammalian species to leukotoxin- and opsonin-treated living and killed Pasteurella haemolytica and Staphylococcus aureus. Am J Vet Res 47, 67\u201374 (1986).","journal-title":"Am J Vet Res"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.35.1.91-94.1982"},{"key":"e_1_3_3_22_2","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.2460\/ajvr.1985.46.11.2253","article-title":"Importance of neutrophils in the pathogenesis of acute pneumonic pasteurellosis in calves","volume":"46","author":"Slocombe RJ","year":"1985","unstructured":"RJ Slocombe, J Marark, R Ingersoll, FJ Derksen, NE Robinson, Importance of neutrophils in the pathogenesis of acute pneumonic pasteurellosis in calves. Am J Vet Res 46, 2258 (1985).","journal-title":"Am J Vet Res"},{"key":"e_1_3_3_23_2","first-page":"D1128","article-title":"Molecular genetic analysis of virulence in Mannheimia (Pasteurella) haemolytica","volume":"1","author":"Highlander SK","year":"2001","unstructured":"SK Highlander, Molecular genetic analysis of virulence in Mannheimia (Pasteurella) haemolytica. Front Biosci 1, D1128\u2013D1150 (2001).","journal-title":"Front Biosci"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1079\/AHRR200242"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1006\/mpat.1998.0236"},{"key":"e_1_3_3_26_2","first-page":"161","article-title":"The leukotoxin of Pasteurella haemolytica binds to \u03b22-integrins on bovine leukocytes","volume":"179","author":"Ambagala T","year":"1999","unstructured":"T Ambagala, APN Ambagala, S Srikumaran, The leukotoxin of Pasteurella haemolytica binds to \u03b22-integrins on bovine leukocytes. FEMS Microbiol Lett 179, 161\u2013167 (1999).","journal-title":"FEMS Microbiol Lett"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0378-1135(99)00040-1"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.1.72-79.2000"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s000180050183"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.275.12.8959"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.70.9.5058-5068.2002"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.7589\/0090-3558-43.1.75"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00808-07"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2007.01.002"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.9.6179-6182.2005"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199909150-00015"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0196-9781(00)00255-2"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.4.881"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1983.tb07424.x"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M601554200"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2005.02.005"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.2007.00818.x"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910180405"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910230202"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M601554200"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.4.881"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)41873-X"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/0882-4010(91)90086-P"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0906775106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T16:02:31Z","timestamp":1739289751000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0906775106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,9,8]]},"references-count":48,"journal-issue":{"issue":"36","published-print":{"date-parts":[[2009,9,8]]}},"alternative-id":["10.1073\/pnas.0906775106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0906775106","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,9,8]]},"assertion":[{"value":"2009-06-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-09-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}