Activation of Caspase-1 in the Nucleus Requires Nuclear Translocation of Pro-caspase-1 Mediated by Its Prodomain

• Published in: The Journal of biological chemistry 1998-09, Vol.273 (37), p.23621-23624
• Main Authors: Mao, Pei-Lin, Jiang, Yalin, Wee, Boon Yu, Porter, Alan G.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Apoptosis; Breast Neoplasms; Caspase 1; Caspases; Cell Line; Cell Nucleus - enzymology; Cysteine Endopeptidases - metabolism; Cytosol - enzymology; Enzyme Activation; Enzyme Precursors - metabolism; Epitopes - analysis; Epitopes - chemistry; Female; HeLa Cells; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Polymerase Chain Reaction; Protein Processing, Post-Translational; Recombinant Proteins - metabolism; Recombinant Proteins - pharmacology; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.37.23621

The interleukin-1β-converting enzyme-like protease precursor, pro-caspase-1, has an N-terminal prodomain that is removed during cleavage activation of the protease. Here we show that tumor necrosis factor treatment of HeLa cells induced apoptosis without detectable proteolytic activation of caspase-1 in the cytosol. Instead, tumor necrosis factor induced the translocation of pro-caspase-1 to the nucleus where it was proteolytically activated, releasing the intact prodomain. We identified a nuclear localization signal in the prodomain, which was required for translocation of both pro-caspase-1 as well as its prodomain to the nucleus. Surprisingly, transfected MCF-7 carcinoma or embryonic kidney 293T cells expressing the prodomain alone underwent apoptosis. These results show that death signal-induced nuclear targeting is a novel activity of a caspase prodomain and indicate that caspase-1 and its prodomain may have hitherto unsuspected nuclear functions in apoptosis.