Sidechain biology and the immunogenicity of PDC-E2, the major autoantigen of primary biliary cirrhosis.
The E2 component of mitochondrial pyruvate dehydrogenase complex (PDC-E2) is the immunodominant autoantigen of primary biliary cirrhosis. Whereas lipoylation of PDC-E2 is essential for enzymatic activity and predominates under normal conditions, other biochemical systems exist that also target the lysine residue, including acylation of fatty acids or xenobiotics and ubiquitinylation. More importantly, the immunogenicity can be affected by derivatization of the lysine residue, as the recognition of lipoylated PDC-E2 by patient autoantibodies is enhanced compared with octanoylated PDC-E2. Furthermore, our laboratory has shown that various xenobiotic modifications of a peptide representing the immunodominant region of PDC-E2 are immunoreactive against patient sera. The only purported regulatory system that prevents the accumulation of potentially autoreactive PDC-E2 is glutathionylation, in which the lysine-lipoic acid moiety is further modified with glutathione during apoptosis. Interestingly, this system is found in several cell lines, including HeLa, Jurkat, and Caco-2 cells, but not in cholangiocytes and salivary gland epithelial cells, both of which are targets for destruction in primary biliary cirrhosis. Hence, the failure of this or other regulatory system(s) may overwhelm the immune system with immunogenic PDC-E2 that can initiate the breakdown of tolerance in a genetically susceptible individual. In this review the authors survey the data available on the biochemical life of PDC-E2, with particular emphasis on the lysine residue and its known interactions with machinery involved in various posttranslational modifications.
Mao
Tin K
TK
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
Davis
Paul A
PA
Odin
Joseph A
JA
Coppel
Ross L
RL
Gershwin
M Eric
ME
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
D001324:Autoantigens; D011768:Pyruvate Dehydrogenase Complex; D051047:Dihydrolipoyllysine-Residue Acetyltransferase