Caspase cleavage of the nuclear autoantigen LEDGF/p75 abrogates its pro-survival function: implications for autoimmunity in atopic disorders.
Lens epithelium-derived growth factor p75 (LEDGF/p75) is a nuclear autoantigen in atopic disorders implicated in cellular protection against stress-induced apoptosis. We observed that LEDGF/p75 was cleaved during apoptosis into fragments of 65 and 58 kD generated by caspases-3 and -7 cleaving at three sites: DEVPD30/G, DAQD486/G and WEID85/N. Sequence analysis revealed that the DEVPD30/G and WEID85/N sites lie within the highly conserved HATH (homologous to amino terminus of hepatoma-derived growth factor) region, also known as PWWP domain. Alignment of proteins containing this domain failed to reveal conservation of the DEVPD30/G and WEID85/N sites, suggesting that the HATH/PWWP domain of LEDGF/p75 may be specifically targeted by caspases. Overexpression of LEDGF/p75 protected HepG2 cells from serum starvation-induced cell death, whereas expression of the 65 kD fragment failed to protect. The apoptotic cleavage of LEDGF/p75 may contribute to the pathogenesis of atopic disorders by abrogating its pro-survival function and enhancing its immunogenicity.
Department of Biochemistry and Microbiology, Center for Molecular Biology and Gene Therapy, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
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Wu
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Daniels
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Molinaro
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Lilly
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Casiano
D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001249:Asthma / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D001665:Binding Sites / Q000235:genetics; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000276:immunology*; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003876:Dermatitis, Atopic / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D012220:Rhinitis / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D016895:Culture Media, Serum-Free; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; C119380:lens epithelium-derived growth factor; D010447:Peptide Hydrolases; C505407:CASP3 protein, human; C505520:CASP7 protein, human; D053148:Caspase 3; D053179:Caspase 7; D020169:Caspases