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J. Biol. Chem., Vol. 280, Issue 18, 18498-18503, May 6, 2005

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Asparagine Deamidation Perturbs Antigen Presentation on Class II Major Histocompatibility Complex Molecules^*

Catherine X. Moss, Stephen P. Matthews, Douglas J. Lamont, and Colin Watts¶

From the Division of Cell Biology and Immunology and the School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom

Post-translational protein modifications can be recognized by B and T lymphocytes and can potentially make "self"-proteins appear foreign to the immune system. Such modifications may directly affect major histocompatibility complex-restricted T cell recognition of processed peptides or may perturb the processing events that generate such peptides. Using the tetanus toxin C fragment protein as a test case, we show that spontaneous deamidation of asparagine residues interferes with processing by the enzyme asparagine endopeptidase (AEP) and contributes to diminished antigen presentation. Deamidation inhibits AEP action either directly, when asparagine residues targeted by AEP are modified, or indirectly, when adjacent Asn residues are deamidated. Thus, deamidation of long-lived self-proteins may qualitatively or quantitatively affect the spectrum of self-peptides displayed to T cells and may thereby contribute to the onset or exacerbation of autoimmune disease.

Received for publication, February 2, 2005 , and in revised form, March 1, 2005.

^* This work was supported by a Wellcome Trust Programme grant (to C. W.) and by a Wellcome Travelling Fellowship (to C. X. M.). 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. Tel.: 44-1382-344233; Fax: 44-1382-345783; E-mail: c.watts{at}dundee.ac.uk.

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