Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis.
Novosphingobium aromaticivorans, a unique ubiquitous bacterium that metabolizes xenobiotics and activates environmental estrogens, has been suggested as a pathogenic factor in the development of primary biliary cirrhosis (PBC). To define the molecular basis of PBC sera reactivity, we investigated the characteristic of the bacterial antigens involved. We cloned and sequenced four genes from N. aromaticivorans coding for immunoreactive proteins, arbitrarily named Novo 1 through Novo 4. We subsequently analyzed these proteins for their homology to known mitochondrial proteins and defined their reactivity using monoclonal antibodies (mAbs), rabbit anti-lipoic acid antibody, and PBC/control sera. Moreover, we studied their phylogenetic relation with the known PBC autoantigens. Novo proteins have an extraordinary degree of amino acid homology with all of the major human mitochondrial autoantigens PDC-E2 (Novo 1 and 2), OGDC-E2 (Novo 3), and BCOADC-E2 (Novo 4). Moreover, Novo 1-4 contain a lipoylated domain, are recognized by AMA-positive sera, and react with specific mAbs to mitochondrial antigens. Interestingly, the phylogenetic relation of the proteins emphasizes the conservation of the lipoylated domain. In conclusion, our data provide a high degree of confidence that N. aromaticivorans may potentiate the breakdown of self tolerance in genetically susceptible individuals.
Padgett
Kerstien A
KA
Division of Rheumatology, Allergy and Clinical Immunology, University of California School of Medicine, GBSF, 451 E. Health Sciences Drive, Suite 6510, Davis, California 95616, USA.
Selmi
Carlo
C
Kenny
Thomas P
TP
Leung
Patrick S C
PS
Balkwill
David L
DL
Ansari
Aftab A
AA
Coppel
Ross L
RL
Gershwin
M Eric
ME
D000217:Acyltransferases / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics* / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D001426:Bacterial Proteins / Q000235:genetics* / Q000276:immunology; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D019143:Evolution, Molecular; D006801:Humans; D008074:Lipoproteins / Q000235:genetics* / Q000276:immunology; D008105:Liver Cirrhosis, Biliary / Q000235:genetics / Q000276:immunology; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D010802:Phylogeny; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D042301:Sphingomonadaceae / Q000235:genetics* / Q000276:immunology; D008063:Thioctic Acid / Q000235:genetics / Q000276:immunology
D000942:Antigens, Bacterial; D001324:Autoantigens; D001426:Bacterial Proteins; D008074:Lipoproteins; D011768:Pyruvate Dehydrogenase Complex; D008063:Thioctic Acid; D000217:Acyltransferases; C033588:dihydrolipoamide acyltransferase; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; C021515:dihydrolipoamide succinyltransferase