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J. Biol. Chem., Vol. 280, Issue 18, 17573-17578, May 6, 2005

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Testing the Role of gp96 as Peptide Chaperone in Antigen Processing^*

Rodion Demine and Peter Walden

From the Charité-University Medicine Berlin, Humboldt University, Clinical Research Group Tumor Immunology, Department of Dermatology and Allergy, D-10098 Berlin, Germany

gp96 is a 96-kDa glycoprotein of the endoplasmic reticulum that is believed to be involved in antigen processing as an intermediate carrier of peptides for presentation by major histocompatibility complex (MHC) class I molecules. This function implies that gp96 carries a large array of different peptides that represent the antigenicity of the cell and can serve all MHC class I molecules. So far, the evidence regarding these peptides is largely indirect and based on experiments where mice immunized with gp96 from tumor or virus-infected cells developed T cellular immune responses with the corresponding specificities. We analyzed by mass spectrometry peptides isolated from gp96 and found a number of different peptides derived from the proteins of different cellular compartments but mostly cytoplasm and nucleus. The sequences of these peptides provide information on the specificity of antigen processing and reveal structural requirements for binding to gp96 that only partially correspond to those of peptides presented by MHC class I molecules. The yield of peptides extracted from gp96 was far substoichiometric with an estimated occupancy of this chaperone of between 0.1% and 0.4%. These results strongly argue against a regular role for gp96 as a peptide chaperone in antigen processing.

Received for publication, February 2, 2005 , and in revised form, February 18, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants KFO 050-TP 1, Kl 427/11-1, and FOR299/1-2-TP 4. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Charité-University Medicine Berlin, Humboldt University, Dept. of Dermatology, Schumannstr. 20/21, D-10117 Berlin, Germany. Tel.: 49-30-450-518-031; Fax: 49-30-450-518-932; E-mail: peter.walden{at}charite.de.

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