Inhibition of ubiquitin/proteasome-dependent protein degradation by the Gly-Ala repeat domain of the Epstein-Barr virus nuclear antigen 1.

Proc Natl Acad Sci U S A 1997 Nov;94(23):12616-21

Microbiology and Tumor Biology Center, Karolinska Institute, Box 280, S-171 77 Stockholm, Sweden.

The Epstein-Barr virus (EBV) encoded nuclear antigen (EBNA) 1 is expressed in latently infected B lymphocytes that persist for life in healthy virus carriers and is the only viral protein regularly detected in all EBV associated malignancies. The Gly-Ala repeat domain of EBNA1 was shown to inhibit in cis the presentation of major histocompatibility complex (MHC) class I restricted cytotoxic T cell epitopes from EBNA4. It appears that the majority of antigens presented via the MHC I pathway are subject to ATP-dependent ubiquitination and degradation by the proteasome. We have investigated the influence of the repeat on this process by comparing the degradation of EBNA1, EBNA4, and Gly-Ala containing EBNA4 chimeras in a cell-free system. EBNA4 was efficiently degraded in an ATP/ubiquitin/proteasome-dependent fashion whereas EBNA1 was resistant to degradation. Processing of EBNA1 was restored by deletion of the Gly-Ala domain whereas insertion of Gly-Ala repeats of various lengths and in different positions prevented the degradation of EBNA4 without appreciable effect on ubiquitination. Inhibition was also achieved by insertion of a Pro-Ala coding sequence. The results suggest that the repeat may affect MHC I restricted responses by inhibiting antigen processing via the ubiquitin/proteasome pathway. The presence of regularly interspersed Ala residues appears to be important for the effect.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC25057PMC
http://dx.doi.org/10.1073/pnas.94.23.12616DOI Listing
November 1997

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References

(Supplied by CrossRef)

Masucci et al.
Trends in microbiology 1994

Steven et al.
Journal of Experimental Medicine 1996

Murray et al.
Journal of Experimental Medicine 1992

Khanna et al.
Journal of Experimental Medicine 1992

Trivedi et al.
International journal of cancer. Journal international du cancer 1991

Levitskaya et al.
Nature; Physical Science (London) 1995

Townsend et al.
Cell 1986

Michalek et al.
Nature; Physical Science (London) 1993

Rock et al.
Cell 1994

Cerundolo et al.
European journal of immunology 1997

Hershko et al.
PNAS 1987

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