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Stimulation splicing, IRES translation, and intron‐less gene are novel mechanisms in generation of self antigens
Author(s) -
Yang XiaoFeng,
Yan Yan,
Xiong Zeyu,
Wang Hong
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1079.28
Subject(s) - rna splicing , intron , immunogenicity , biology , internal ribosome entry site , alternative splicing , exon , antigen , gene , gene isoform , epitope , microbiology and biotechnology , minigene , translation (biology) , genetics , messenger rna , rna
The question of how non‐mutated self‐tumor antigens (>2,000) and autoantigens (>200) gain immunogenicity remained poorly defined. To address this issue, we first identified the isoform of tumor antigen CML66, CML66L, is the immunodominant isoform, suggesting that alternative splicing is an important mechanism in regulation of immunogenicity of the antigen (Yan Y et al , J. Immunol. 2004). We also found that alternative splicing modulates 100% of 45 autoantigens, in contrast to 42% of the rates of alternative splicing for processing randomly‐selected genes. Therefore, we propose a novel model of stimulation‐responsive splicing for generation of untolerized spliced isoforms of self‐antigens (Yang F et al , Clin. Immunol. 2006), which suggests that in response to various stimuli, alternative splicing provides structural basis for expression of untolerized antigen epitopes. Furthermore, we demonstrated that a novel tumor antigen, MPD6, elicits immune responses against myeloid malignancies. MPD6 is encoded by a secondary open reading frame (ORF) of the gene, and its translation is driven by a new internal ribosome entry site (IRES) (Xiong Z et al , J. Immunol. 2006). Finally, we identified a novel tumor antigen, MPD5, which is encoded by an intron‐less gene located in NEK6 gene locus (Xiong Z et al , Intl. J. Immunopathol. Pharmacol. 2007). Taken together, we have identified three novel mechanisms, alternative splicing, IRES‐driven secondary ORF translation, and intron‐less gene transcription, for generation of immunogenicity of self‐tumor antigens and autoantigens. These findings provide novel insights in development of more effective immunotherapy for tumors and autoimmune diseases.