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© The Rockefeller University Press, 0021-9525/1999//113 $5.00
The Journal of Cell Biology, Volume 146, Number 1, , 1999 113-124

Intracellular Localization of Proteasomal Degradation of a Viral Antigen

^a Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892
^b Heinrich-Pette Institute, University of Hamburg, Hamburg, Germany
^c Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland 20892
^d Department of Biochemistry, University of Utah, Salt Lake City, Utah 84112
Room 213, Building 4, 4 Center Drive, NIH, Bethesda, MD 20892-0440.301-402-7362301-402-4602

jyewdell{at}nih.gov

jbennink{at}nih.gov

To better understand proteasomal degradation of nuclear proteins and viral antigens we studied mutated forms of influenza virus nucleoprotein (NP) that misfold and are rapidly degraded by proteasomes. In the presence of proteasome inhibitors, mutated NP (dNP) accumulates in highly insoluble ubiquitinated and nonubiquitinated species in nuclear substructures known as promyelocytic leukemia oncogenic domains (PODs) and the microtubule organizing center (MTOC). Immunofluorescence revealed that dNP recruits proteasomes and a selective assortment of molecular chaperones to both locales, and that a similar (though less dramatic) effect is induced by proteasome inhibitors in the absence of dNP expression. Biochemical evidence is consistent with the idea that dNP is delivered to PODs/MTOC in the absence of proteasome inhibitors. Restoring proteasome activity while blocking protein synthesis results in disappearance of dNP from PODs and the MTOC and the generation of a major histocompatibility complex class I–bound peptide derived from dNP but not NP. These findings demonstrate that PODs and the MTOC serve as sites of proteasomal degradation of misfolded dNP and probably cellular proteins as well, and imply that antigenic peptides are generated at one or both of these sites.

Key Words: antigen presentation • molecular • chaperone • nuclear proteins proteolysis • ubiquitin/immunology • proteasome

© 1999 The Rockefeller University Press

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