Unique conformation of cancer autoantigen B23 in hepatoma: A mechanism for specificity in the autoimmune response

Danielle B. Ulanet, Michael Torbenson, Chi V. Dang, Livia Casciola-Rosen, Antony Rosen

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

The association of a specific autoantibody response with distinct disease phenotypes is observed in both autoimmune diseases and cancer. Although the underlying mechanisms remain unclear, it is likely that unique properties of disease-specific autoantigens expressed in the relevant target cells play a role. It has recently been observed that the majority of autoantigens targeted across the spectrum of systemic autoimmune diseases (but not nonautoantigens) are selectively cleaved by the cytotoxic lymphocyte granule protease granzyme B (GB), generating unique fragments not observed during other forms of cell death. Although susceptibility of a molecule to cleavage by GB strongly predicts autoantigen status, the significance of this association is unclear. We used hepatocellular carcinoma and the hepatocellular carcinoma autoantigen, nucleophosmin/B23, as a model system to define the unique features of disease-specific autoantigens in the relevant disease microenvironment. These studies revealed a striking, selective susceptibility of B23 to cleavage by GB in extracts of neoplastic liver. The increased sensitivity of tumor B23 to proteolysis by GB was accompanied by slightly increased mobility on SDS/PAGE, altered subcellular localization, enrichment of an SDS-stable oligomeric form of B23, and recognition by a conformation-specific antibody detecting a B23 epitope ending at the GB cleavage site. In vitro studies demonstrated that this unique B23 conformation and resultant increased susceptibility to cleavage by GB arise when B23 translation is initiated at methionine-7. We propose that unique features of autoantigens in the disease-relevant microenvironment may regulate susceptibility to cleavage by GB and their selection by the specific autoimmune response.

Original languageEnglish (US)
Pages (from-to)12361-12366
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number21
DOIs
StatePublished - Oct 14 2003
Externally publishedYes

    Fingerprint

Keywords

  • Granzyme B
  • Hepatocellular carcinoma
  • Nucleolus
  • Oligomer
  • Proteolysis

ASJC Scopus subject areas

  • General

Cite this