A polyadenylate binding protein localized to the granules of cytolytic lymphocytes induces DNA fragmentation in target cells.
Cytolytic lymphocytes (CTLs) are characterized by their inclusion of cytoplasmic granules containing effector molecules such as perforin and the serine proteases. Here we describe the cDNA cloning and functional characterization of two related isoforms of a cytolytic granule protein designated TIA-1. Sequence analysis reveals that the 40 kd TIA-1 isoform (rp40-TIA-1) is structurally related to the poly(A)-binding proteins, possessing three RNA-binding domains and a carboxy-terminal, glutamine-rich auxiliary domain. The 15 kd TIA-1 isoform, the major species present in cytolytic granules, appears to be derived from the carboxy-terminal auxiliary domain of rp40-TIA-1 by proteolytic processing. Both natural and recombinant TIA-1 were found to induce DNA fragmentation in digitonin permeabilized thymocytes, suggesting that these molecules may be the granule components responsible for inducing apoptosis in CTL targets.
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115.
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Tian
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Streuli
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Saito
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Schlossman
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Anderson
D000595:Amino Acid Sequence; D001483:Base Sequence; D015152:Blotting, Northern; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D015870:Gene Expression; D007694:Killer Cells, Natural / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins; D016415:Sequence Alignment; D000074019:T-Cell Intracellular Antigen-1; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*
D002352:Carrier Proteins; D008565:Membrane Proteins; D039102:Poly(A)-Binding Proteins; D011506:Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; D004247:DNA