Heteronuclear ribonucleoproteins C1 and C2, components of the spliceosome, are specific targets of interleukin 1beta-converting enzyme-like proteases in apoptosis.
Apoptosis induced by a variety of agents results in the proteolytic cleavage of a number of cellular substrates by enzymes related to interleukin 1beta-converting enzyme (ICE). A small number of substrates for these enzymes have been identified to date, including enzymes involved in DNA repair processes: poly(ADP-ribose) polymerase and DNA-dependent protein kinase. We describe here for the first time the specific cleavage of the heteronuclear ribonucleoproteins (hnRNPs) C1 and C2 in apoptotic cells induced to undergo apoptosis by a variety of stimuli, including ionizing radiation, etoposide, and ceramide. No cleavage was observed in cells that are resistant to apoptosis induced by ionizing radiation. Protease inhibitor data implicate the involvement of an ICE-like protease in the cleavage of hnRNP C. Using recombinant ICE-like proteases and purified hnRNP C proteins in vitro, we show that the C proteins are cleaved by Mch3alpha and CPP32 and, to a lesser extent, by Mch2alpha, but not by ICE, Nedd2, Tx, or the cytotoxic T-cell protease granzyme B. The results described here demonstrate that the hnRNP C proteins, abundant nuclear proteins thought to be involved in RNA splicing, belong to a critical set of protein substrates that are cleaved by ICE-like proteases during apoptosis.
Waterhouse
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N
Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, P. O. Royal Brisbane Hospital, Herston, Brisbane, Queensland 4029, Australia. dianneW@qimr.edu.au
Kumar
S
S
Song
Q
Q
Strike
P
P
Sparrow
L
L
Dreyfuss
G
G
Alnemri
E S
ES
Litwack
G
G
Lavin
M
M
Watters
D
D
D017209:Apoptosis; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D006801:Humans; D006868:Hydrolysis; D011836:Radiation Tolerance; D012261:Ribonucleoproteins / Q000378:metabolism*; D017381:Spliceosomes / Q000378:metabolism*; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
C439788:C1 HNRNP; C503635:HNRNPC protein, human; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D034441:Heterogeneous-Nuclear Ribonucleoproteins; D012261:Ribonucleoproteins; D003546:Cysteine Endopeptidases; D020170:Caspase 1