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PMID: 10432301 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Caspase-mediated cleavage of eukaryotic translation initiation factor subunit 2alpha.

The Biochemical journal ·Vol. 342 ( Pt 1) ·1999-08-15 ·Pages 65-70

Satoh S, Hijikata M, Handa H, Shimotohno K

Abstract

Eukaryotic translation initiation factor 2alpha (eIF-2alpha), a target molecule of the interferon-inducible double-stranded-RNA-dependent protein kinase (PKR), was cleaved in apoptotic Saos-2 cells on treatment with poly(I).poly(C) or tumour necrosis factor alpha. This cleavage occurred with a time course similar to that of poly(ADP-ribose) polymerase, a well-known caspase substrate. In addition, eIF-2alpha was cleaved by recombinant active caspase-3 in vitro. By site-directed mutagenesis, the cleavage site was mapped to an Ala-Glu-Val-Asp(300) downward arrowGly(301) sequence located in the C-terminal portion of eIF-2alpha. PKR phosphorylates eIF-2alpha on Ser(51), resulting in the suppression of protein synthesis. PKR-mediated translational suppression was repressed when the C-terminally cleaved product of eIF-2alpha was overexpressed in Saos-2 cells, even though PKR can phosphorylate this cleaved product. These results suggest that caspase-3 or related protease(s) can modulate the efficiency of protein synthesis by cleaving the alpha subunit of eIF-2, a key component in the initiation of translation.

MeSH Terms
Apoptosis/drug effects Caspase 3 Caspase Inhibitors Caspases/genetics,metabolism Cycloheximide/pharmacology Eukaryotic Initiation Factor-2/chemistry,genetics,metabolism Humans Kinetics Mutagenesis, Site-Directed Phosphorylation Phosphoserine/metabolism Poly I-C/pharmacology Poly(ADP-ribose) Polymerases/metabolism Protein Biosynthesis Recombinant Fusion Proteins/chemistry,genetics,metabolism Sequence Deletion Tumor Cells, Cultured Tumor Necrosis Factor-alpha/pharmacology eIF-2 Kinase/metabolism
Chemicals
Caspase Inhibitors Eukaryotic Initiation Factor-2 Recombinant Fusion Proteins Tumor Necrosis Factor-alpha Phosphoserine Cycloheximide Poly(ADP-ribose) Polymerases eIF-2 Kinase CASP3 protein, human Caspase 3 Caspases Poly I-C
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Satoh S
Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Hijikata M
Handa H
Shimotohno K
References (38)
38 references, click to expand
  1. Cleavage of structural proteins during the assembly of the head of bacteriophage T4.
    Nature. 1970 Aug 15;227(5259):680-5 PMID: 5432063
  2. Phosphorylation of nonstructural 5A protein of hepatitis C virus: HCV group-specific hyperphosphorylation.
    Virology. 1999 Apr 25;257(1):130-7 PMID: 10208927
  3. Initiation of protein synthesis in mammalian cells.
    Biochem J. 1986 May 1;235(3):625-37 PMID: 3530248
  4. Detection of activated double-stranded RNA-dependent protein kinase in 3T3-F442A cells.
    Proc Natl Acad Sci U S A. 1988 Mar;85(5):1427-31 PMID: 2449691
  5. Generation of a mutant form of protein synthesis initiation factor eIF-2 lacking the site of phosphorylation by eIF-2 kinases.
    Mol Cell Biol. 1988 Feb;8(2):993-5 PMID: 3352609
  6. The phosphorylation state of eucaryotic initiation factor 2 alters translational efficiency of specific mRNAs.
    Mol Cell Biol. 1989 Mar;9(3):946-58 PMID: 2657393
  7. Cloning of the cDNA of the heme-regulated eukaryotic initiation factor 2 alpha (eIF-2 alpha) kinase of rabbit reticulocytes: homology to yeast GCN2 protein kinase and human double-stranded-RNA-dependent eIF-2 alpha kinase.
    Proc Natl Acad Sci U S A. 1991 Sep 1;88(17):7729-33 PMID: 1679235
  8. Stimulation of protein synthesis in COS cells transfected with variants of the alpha-subunit of initiation factor eIF-2.
    J Biol Chem. 1992 Jan 5;267(1):286-93 PMID: 1346129
  9. Human p68 kinase exhibits growth suppression in yeast and homology to the translational regulator GCN2.
    EMBO J. 1992 Apr;11(4):1553-62 PMID: 1348691
  10. Constitutive expression of human double-stranded RNA-activated p68 kinase in murine cells mediates phosphorylation of eukaryotic initiation factor 2 and partial resistance to encephalomyocarditis virus growth.
    J Virol. 1992 Oct;66(10):5805-14 PMID: 1382142
  11. The eIF-2 alpha protein kinases, regulators of translation in eukaryotes from yeasts to humans.
    J Biol Chem. 1993 Apr 15;268(11):7603-6 PMID: 8096514
  12. The interferon-induced double-stranded RNA-activated human p68 protein kinase potently inhibits protein synthesis in cultured cells.
    Virology. 1993 Jan;192(1):380-5 PMID: 7685968
  13. Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus.
    J Virol. 1993 Aug;67(8):4665-75 PMID: 8392606
  14. Mutations in the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2 alpha) that overcome the inhibitory effect of eIF-2 alpha phosphorylation on translation initiation.
    Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7215-9 PMID: 8102207
  15. Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus.
    Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10773-7 PMID: 7504283
  16. The interferon-induced double-stranded RNA-activated protein kinase induces apoptosis.
    Virology. 1994 Mar;199(2):491-6 PMID: 7510087
  17. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE.
    Nature. 1994 Sep 22;371(6495):346-7 PMID: 8090205
  18. Specific cleavage of the 70-kDa protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death.
    J Biol Chem. 1994 Dec 9;269(49):30757-60 PMID: 7983001
  19. Apoptosis in the pathogenesis and treatment of disease.
    Science. 1995 Mar 10;267(5203):1456-62 PMID: 7878464
  20. Studies of the lamin proteinase reveal multiple parallel biochemical pathways during apoptotic execution.
    Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9042-6 PMID: 7568069
  21. Apoptosis: molecular regulation of cell death.
    Eur J Biochem. 1996 Feb 15;236(1):1-26 PMID: 8617251
  22. Initiation of protein synthesis in eukaryotic cells.
    Eur J Biochem. 1996 Mar 15;236(3):747-71 PMID: 8665893
  23. DNA-dependent protein kinase catalytic subunit: a target for an ICE-like protease in apoptosis.
    EMBO J. 1996 Jul 1;15(13):3238-46 PMID: 8670824
  24. Replication of hepatitis C virus in cultured non-neoplastic human hepatocytes.
    Jpn J Cancer Res. 1996 Aug;87(8):787-92 PMID: 8797883
  25. Human ICE/CED-3 protease nomenclature.
    Cell. 1996 Oct 18;87(2):171 PMID: 8861900
  26. Activation of multiple interleukin-1beta converting enzyme homologues in cytosol and nuclei of HL-60 cells during etoposide-induced apoptosis.
    J Biol Chem. 1997 Mar 14;272(11):7421-30 PMID: 9054443
  27. Processing/activation of at least four interleukin-1beta converting enzyme-like proteases occurs during the execution phase of apoptosis in human monocytic tumor cells.
    J Cell Biol. 1997 Apr 21;137(2):469-79 PMID: 9128256
  28. Characterization of peripheral blood T-lymphocytes transduced with HTLV-I Tax mutants with different trans-activating phenotypes.
    Oncogene. 1997 May 1;14(17):2071-8 PMID: 9160887
  29. Multiple species of CPP32 and Mch2 are the major active caspases present in apoptotic cells.
    EMBO J. 1997 May 1;16(9):2271-81 PMID: 9171342
  30. Affinity labeling displays the stepwise activation of ICE-related proteases by Fas, staurosporine, and CrmA-sensitive caspase-8.
    Oncogene. 1997 Jun 12;14(23):2741-52 PMID: 9190889
  31. Retinoid-induced apoptosis and Sp1 cleavage occur independently of transcription and require caspase activation.
    Mol Cell Biol. 1997 Nov;17(11):6348-58 PMID: 9343396
  32. Identification of interprotein interactions between the subunits of eukaryotic initiation factors eIF2 and eIF2B.
    J Biol Chem. 1998 Jan 30;273(5):3039-44 PMID: 9446619
  33. Inhibition of tumor necrosis factor (TNF-alpha)-mediated apoptosis by hepatitis C virus core protein.
    J Biol Chem. 1998 Jan 23;273(4):2256-9 PMID: 9442069
  34. Phosphorylation of eukaryotic translation initiation factor 2 mediates apoptosis in response to activation of the double-stranded RNA-dependent protein kinase.
    J Biol Chem. 1998 Jan 23;273(4):2416-23 PMID: 9442091
  35. STAT1 is inactivated by a caspase.
    J Biol Chem. 1998 Apr 10;273(15):8699-704 PMID: 9535846
  36. Eukaryotic translation initiation factor 4G is targeted for proteolytic cleavage by caspase 3 during inhibition of translation in apoptotic cells.
    Mol Cell Biol. 1998 Dec;18(12):7565-74 PMID: 9819442
  37. A 60 kd MDM2 isoform is produced by caspase cleavage in non-apoptotic tumor cells.
    Oncogene. 1998 Nov 19;17(20):2629-36 PMID: 9840926
  38. Growth-related expression of a double-stranded RNA-dependent protein kinase in 3T3 cells.
    J Biol Chem. 1984 Dec 10;259(23):14736-42 PMID: 6501315
Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
0264-6021
Published
1999-08-15
Pages
65-70
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1220437
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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