Human RNA helicase A is a lupus autoantigen that is cleaved during apoptosis.
Proteolytic cleavage by caspases is the central event in cells undergoing apoptosis. Cleaved proteins are often targeted by autoantibodies, suggesting that the cleavage of self Ags enhances immunogenicity and is prone to induce an autoimmune response. We found autoantibodies that immunoprecipitated a 140-kDa RNA-associated protein, provisionally designated Pa, in 11 of 350 patient sera that were positive for antinuclear Abs in an immunofluorescence test. The Pa protein gave rise to three fragments with m.w. ranging from 120-130 kDa during anti-Fas-activated apoptosis. Pure caspase-3 cleaved the Pa protein into a 130-kDa fragment corresponding to the largest of these three products. Peptide sequence analysis of a tryptic digest from immunoaffinity-purified Pa showed 100% identity to human RNA helicase A (RHA). The identity of Pa with RHA was further confirmed by immunoblotting with rabbit anti-RHA Ab using anti-Pa immunoprecipitates as substrates. All 10 anti-RHA-positive patients who were clinically analyzed were diagnosed as having systemic lupus erythematosus, and 7 of them had lupus nephritis. RHA is a multifunctional protein with roles in cellular RNA synthesis and processing. Inactivation of RHA by cleavage may be an important part of the process leading to programmed cell death. The cleaved RHA fragments that are produced during apoptosis may trigger an autoimmune response in systemic lupus erythematosus.
Takeda
Y
Y
Program in Gene Regulation, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA. ytakeda@mail.mc.edu
Caudell
P
P
Grady
G
G
Wang
G
G
Suwa
A
A
Sharp
G C
GC
Dynan
W S
WS
Hardin
J A
JA
D000595:Amino Acid Sequence; D017209:Apoptosis; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D053487:DEAD-box RNA Helicases; D006367:HeLa Cells; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D010446:Peptide Fragments / Q000737:chemistry; D020365:RNA Helicases / Q000276:immunology* / Q000378:metabolism; D020539:Sequence Analysis, Protein
D001324:Autoantigens; D009363:Neoplasm Proteins; D010446:Peptide Fragments; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C098487:DHX9 protein, human; D053487:DEAD-box RNA Helicases; D020365:RNA Helicases