Activation of caspase-1 in the nucleus requires nuclear translocation of pro-caspase-1 mediated by its prodomain.
The interleukin-1beta-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.
Mao
P L
PL
Institute of Molecular and Cell Biology, The National University of Singapore, Singapore 117609, Republic of Singapore.
Jiang
Y
Y
Wee
B Y
BY
Porter
A G
AG
D000595:Amino Acid Sequence; D017209:Apoptosis; D001943:Breast Neoplasms; D020170:Caspase 1; D020169:Caspases; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D000939:Epitopes / Q000032:analysis / Q000737:chemistry; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004792:Enzyme Precursors; D000939:Epitopes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D020169:Caspases; D003546:Cysteine Endopeptidases; D020170:Caspase 1