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Tannerella Forsythia Page 1 of 44 Journal of Proteome Research 1 2 3 Revised MS pr-2015-00878s 4 5 6 7 Tannerella forsythia Outer Membrane Vesicles are 8 9 10 11 Enriched with Substrates of the Type IX Secretion 12 13 14 15 System and TonB-dependent Receptors 16 17 18 19 20 21 22 23 24 Paul D. Veith, Yu-Yen Chen, Dina Chen, Neil M. O’Brien-Simpson, Jessica D. Cecil, James 25 26 27 A. Holden, Jason C. Lenzo and Eric C. Reynolds* 28 29 30 31 Oral Health CRC, Melbourne Dental School, Bio21 Institute, The University of Melbourne, 32 33 720 Swanston Street, Melbourne, Victoria, 3010, Australia 34 35 36 37 38 39 40 41 KEYWORDS: Tannerella forsythia; outer membrane vesicles; proteome; cryo-TEM;, 42 43 chronic periodontitis; type IX secretion; TonB-dependent receptors 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 ACS Paragon Plus Environment Journal of Proteome Research Page 2 of 44 1 2 3 ABSTRACT 4 5 6 Tannerella forsythia , a Gram-negative oral bacterium closely associated with chronic 7 8 periodontitis naturally produces outer membrane vesicles (OMVs). In this study, OMVs were 9 10 purified by gradient centrifugation and the proteome was investigated together with cellular 11 12 fractions using LC-MS/MS analyses of SDS-PAGE fractions, resulting in the identification of 13 14 872 proteins including 297 OMV proteins. Comparison of the OMV proteome with the 15 16 17 subcellular proteomes led to the localization of 173 proteins to the vesicle membrane and 61 18 19 proteins to the vesicle lumen while 27 substrates of the type IX secretion system were 20 21 assigned to the vesicle surface. These substrates were generally enriched in OMVs, however 22 23 the stoichiometry of the S-layer proteins, TfsA and TfsB was significantly altered, potentially 24 25 26 to accommodate the higher curvature required of the S-layer around OMVs. A vast number 27 28 of TonB-dependent receptors related to SusC, together with their associated SusD-like 29 30 lipoproteins were identified and these were also relatively enriched in OMVs. In contrast, 31 32 other lipoproteins were significantly depleted from the OMVs. This study identified the 33 34 highest number of membrane associated OMV proteins to date in any bacterium and 35 36 37 conclusively demonstrates cargo sorting of particular classes of proteins which may have 38 39 significant impact on the virulence of OMVs. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 ACS Paragon Plus Environment Page 3 of 44 Journal of Proteome Research 1 2 3 INTRODUCTION 4 5 6 Chronic periodontitis is an inflammatory disease of the supporting tissues of the teeth 7 8 associated with a polymicrobial biofilm (subgingival plaque) accreted to the tooth which 9 10 results in destruction of the tooth’s supporting tissues including the alveolar bone 1. 11 12 Periodontitis has been linked to an increased risk of cardiovascular diseases, certain cancers 13 14 15 (orogastrointestinal tract and pancreas), pre-term birth, low birth weight and other systemic 16 17 diseases related to the regular bacteraemia and chronic inflammation associated with the 18 19 disease 2, 3. Although chronic periodontitis is associated with a polymicrobial biofilm, the 20 21 specific bacterial species of the biofilm Porphyromonas gingivalis, Treponema denticola and 22 23 24 Tannerella forsythia as a consortium have been closely associated with clinical measures of 25 4, 5 6 26 disease . T. forsythia is a Gram-negative, anaerobic, fusiform bacterium . It has been 27 28 demonstrated to cause alveolar bone loss in mice 7 and synergistically caused increased bone 29 30 loss when co-infected with P. gingivalis or Fusobacterium nucleatum in rats 8. T. forsythia 31 32 33 produces several putative protein virulence factors such as proteinases, a surface layer, BspA 34 9 35 and various glycosidases, and these have been reviewed . More recently, a group of six 36 37 secreted proteases sharing a near identical C-terminal domain ending with the amino acid 38 39 sequence KLIKK was identified and proposed to be virulence factors 10 . Of these, the 40 41 metalloproteinases karilysin and mirolysin were shown to inhibit the human complement 42 43 11, 12 44 system by degrading C4, C5 and ficolin while mirolase was shown to degrade human 45 13 46 fibrinogen and the antimicrobial peptide LL-37 . 47 48 A distinctive feature of SDS-PAGE profiles of whole cell extracts of T. forsythia is 49 50 51 the presence of a major double band greater than 200 kDa. These bands correspond to two 52 53 glycoproteins designated surface layer protein A (TfsA) and surface layer protein B (TfsB) 54 55 which are the reported constituents of the surface layer (S-layer), a distinct layer beyond the 56 57 outer membrane (OM) that can be clearly seen in electron micrographs 14, 15 . The structure of 58 59 60 3 ACS Paragon Plus Environment Journal of Proteome Research Page 4 of 44 1 2 3 this 22 nm thick S-layer has been recently probed by both TEM and AFM techniques and is 4 5 described as a P4 structure, with a lattice constant of 9-10 nm resulting from co-assembly of 6 7 equimolar amounts of TfsA and TfsB 16, 17 . In our proteomic analysis of the T. forsythia OM, 8 9 10 we identified 15 putative glycoproteins including TfsA and TfsB which shared a similar C- 11 12 terminal domain sequence (CTD) that was also common to many surface-associated P. 13 14 gingivalis proteins 18 . This sequence is now understood to be the secretion signal for the type 15 16 IX secretion system (T9SS, formerly PorSS 19 ) and has been indirectly shown to be cleaved 17 18 20, 21 22 19 and modified by a novel Gram negative sortase, PorU . Recently, the T. forsythia 20 21 surface layer proteins have been confirmed to be secreted by the T9SS, since the surface layer 22 23 was absent in mutants lacking various components of the T9SS 23, 24 . A study comparing the 24 25 proteomes of T. forsythia grown as a biofilm and as a planktonic culture quantitated the 26 27 relative level of 348 proteins with 44 reported to have changed significantly in abundance 25 . 28 29 30 The proteins that were reduced in abundance in the biofilm included several enzymes 31 32 involved in central metabolism and butyrate production while the proteins that increased in 33 34 abundance were mainly membrane proteins and proteins involved in stress response. 35 36 37 Gram-negative bacteria naturally produce outer membrane vesicles (OMVs) by 38 39 “blebbing” of their OM. OMVs are composed of a single membrane that is derived from the 40 41 outer membrane (OM) and contains OM proteins, lipopolysaccharide, and other lipids, while 42 43 the vesicle lumen mainly contains periplasmic proteins 26 . OMVs are important virulence 44 45 factors being involved in bacterial adherence, defence against host factors, and the delivery of 46 47 26 48 a wide range of toxins . For example, OMVs from enterotoxigenic Escherichia coli 49 50 specifically bind to and enter intestinal epithelial cells thereby delivering its cargo of heat- 51 52 labile enterotoxin 27 . OMVs also play an important role in adhesion in bacterial biofilms 53 54 including biofilms of Pseudomonas aeruginosa and Myxococcus xanthis 28 . OMVs of P. 55 56 29 57 gingivalis are able to bind to T. forsythia , assisting its attachment to epithelial cells . OMVs 58 59 60 4 ACS Paragon Plus Environment Page 5 of 44 Journal of Proteome Research 1 2 3 of periodontal pathogens have been proposed to have a critical role in the pathogenesis of 4 5 periodontitis by being released from the bacteria as components of the biofilm accreted on the 6 7 tooth root and penetrating the host’s gingival tissue whereby they induce vascular disruption 8 9 30-32 10 (bleeding) and immune dysregulation. OMVs are also being developed as vaccines for 11 33 12 different bacterial species . 13 14 It is useful to study the proteomes of OMVs for several purposes including the 15 16 17 characterisation of OMV-based vaccines, identification of virulence factors, OMV biogenesis 18 34 19 and protein localization . Our recent study of the OMV proteome of P. gingivalis for 20 21 example demonstrated that the substrates of the T9SS including toxins such as the gingipain 22 23 proteinases were enriched in OMVs and identified other enriched proteins that may be 24 25 involved in OMV biogenesis 32 . Unlike other OMV proteomes the OMV proteome of P. 26 27 28 gingivalis was very clean with no detectable cytoplasmic contamination and was therefore 29 30 very helpful as a means of determining the cellular localization of proteins to the outer 31 32 membrane or periplasm 32 . In a recent study of the T. forsythia OMV proteome, 175 proteins 33 34 were identified and the OMVs were shown to retain the S-layer and stimulate the release of 35 36 35 37 pro-inflammatory mediators from a human monocytic cell line . In the current study we 38 39 significantly extend the proteomic analysis of T. forsythia OMVs identifying 297 proteins, 40 41 experimentally determining protein localization to the vesicle membrane and lumen and 42 43 providing strong evidence for cargo sorting of particular protein classes. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 5 ACS Paragon Plus Environment Journal of Proteome Research Page 6 of 44 1 2 3 METHODS 4 5 6 Isolation and Enrichment of T.
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