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FACIN, a double-edged sword of the emerging periodontal pathogen filifactor alocis : A metabolic enzyme moonlighting as a complement inhibitor

Jusko, Monika LU ; Miedziak, Beata; Ermert, David LU ; Magda, Michal; King, Ben C. LU ; Bielecka, Ewa LU ; Riesbeck, Kristian LU ; Eick, Sigrun; Potempa, Jan and Blom, Anna M. LU (2016) In Journal of Immunology 197(8). p.3245-3259
Abstract

Periodontal disease is one of the most common inflammatory infectious diseases worldwide and it is associated with other syndromes, such as cardiovascular disease or rheumatoid arthritis. Recent advances in sequencing allowed for identification of novel periodontopathogens such as Gram-positive Filifactor alocis, but its virulence mechanisms remain largely unknown.We confirmed that F. alocis is a prevalent species in periodontitis patients, and we also observed strong correlation of this bacterium with clinical parameters, highlighting its role in the pathogenesis of the disease. Further, we found that preincubation of human serum with F. alocis resulted in abolished bactericidal activity and that F. alocis was surviving readily in full... (More)

Periodontal disease is one of the most common inflammatory infectious diseases worldwide and it is associated with other syndromes, such as cardiovascular disease or rheumatoid arthritis. Recent advances in sequencing allowed for identification of novel periodontopathogens such as Gram-positive Filifactor alocis, but its virulence mechanisms remain largely unknown.We confirmed that F. alocis is a prevalent species in periodontitis patients, and we also observed strong correlation of this bacterium with clinical parameters, highlighting its role in the pathogenesis of the disease. Further, we found that preincubation of human serum with F. alocis resulted in abolished bactericidal activity and that F. alocis was surviving readily in full blood. We demonstrated that one of the key contributors to F. alocis complement resistance is a unique protein, FACIN (F. alocis complement inhibitor), which binds to C3, resulting in suppression of all complement pathways. Interestingly, FACIN is a nonclassical cell surface protein, a cytosolic enzyme acetylornithine transaminase, for which we now identified a moonlighting function. FACIN binds to C3 alone, but more importantly it also captures activated complement factor 3 within the complex with factor B, thereby locking in the convertase in an inactive state. Because of the indispensable role of alternative pathway convertase in amplifying complement cascades, its inhibition by FACIN results in a very potent downregulation of activated complement factor 3 opsonization on the pathogen surface, accompanied by reduction of downstream C5 cleavage.

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organization
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type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
197
issue
8
pages
15 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:84991449356
  • wos:000387965100027
ISSN
0022-1767
DOI
10.4049/jimmunol.1600739
language
English
LU publication?
yes
id
ce9cb397-439d-4529-a706-d13d7b87ed28
date added to LUP
2016-10-31 09:28:36
date last changed
2017-08-13 04:59:44
@article{ce9cb397-439d-4529-a706-d13d7b87ed28,
  abstract     = {<p>Periodontal disease is one of the most common inflammatory infectious diseases worldwide and it is associated with other syndromes, such as cardiovascular disease or rheumatoid arthritis. Recent advances in sequencing allowed for identification of novel periodontopathogens such as Gram-positive Filifactor alocis, but its virulence mechanisms remain largely unknown.We confirmed that F. alocis is a prevalent species in periodontitis patients, and we also observed strong correlation of this bacterium with clinical parameters, highlighting its role in the pathogenesis of the disease. Further, we found that preincubation of human serum with F. alocis resulted in abolished bactericidal activity and that F. alocis was surviving readily in full blood. We demonstrated that one of the key contributors to F. alocis complement resistance is a unique protein, FACIN (F. alocis complement inhibitor), which binds to C3, resulting in suppression of all complement pathways. Interestingly, FACIN is a nonclassical cell surface protein, a cytosolic enzyme acetylornithine transaminase, for which we now identified a moonlighting function. FACIN binds to C3 alone, but more importantly it also captures activated complement factor 3 within the complex with factor B, thereby locking in the convertase in an inactive state. Because of the indispensable role of alternative pathway convertase in amplifying complement cascades, its inhibition by FACIN results in a very potent downregulation of activated complement factor 3 opsonization on the pathogen surface, accompanied by reduction of downstream C5 cleavage.</p>},
  author       = {Jusko, Monika and Miedziak, Beata and Ermert, David and Magda, Michal and King, Ben C. and Bielecka, Ewa and Riesbeck, Kristian and Eick, Sigrun and Potempa, Jan and Blom, Anna M.},
  issn         = {0022-1767},
  language     = {eng},
  month        = {10},
  number       = {8},
  pages        = {3245--3259},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {FACIN, a double-edged sword of the emerging periodontal pathogen filifactor alocis : A metabolic enzyme moonlighting as a complement inhibitor},
  url          = {http://dx.doi.org/10.4049/jimmunol.1600739},
  volume       = {197},
  year         = {2016},
}