The Journal of Experimental Medicine
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A correction to this article has been published: J. Exp. Med. 186 (11) 1945
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© The Rockefeller University Press, 0022-1007/1997/8/549/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 4, August 18, 1997 549-560

Article

Degradation of Mouse Invariant Chain: Roles of Cathepsins S and D and the Influence of Major Histocompatibility Complex Polymorphism

José A. Villadangos*, Richard J. Riese{ddagger}, Christoph Peters§, Harold A. Chapman{ddagger}, and Hidde L. Ploegh*

From the * Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139; {ddagger} Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115; and the § Abteilung Innere Medizin I, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany

Antigen-presenting cells (APC) degrade endocytosed antigens into peptides that are bound and presented to T cells by major histocompatibility complex (MHC) class II molecules. Class II molecules are delivered to endocytic compartments by the class II accessory molecule invariant chain (Ii), which itself must be eliminated to allow peptide binding. The cellular location of Ii degradation, as well as the enzymology of this event, are important in determining the sets of antigenic peptides that will bind to class II molecules. Here, we show that the cysteine protease cathepsin S acts in a concerted fashion with other cysteine and noncysteine proteases to degrade mouse Ii in a stepwise fashion. Inactivation of cysteine proteases results in incomplete degradation of Ii, but the extent to which peptide loading is blocked by such treatment varies widely among MHC class II allelic products. These observations suggest that, first, class II molecules associated with larger Ii remnants can be converted efficiently to class II–peptide complexes and, second, that most class II–associated peptides can still be generated in cells treated with inhibitors of cysteine proteases. Surprisingly, maturation of MHC class II in mice deficient in cathepsin D is unaffected, showing that this major aspartyl protease is not involved in degradation of Ii or in generation of the bulk of antigenic peptides.

Address correspondence to Hidde L. Ploegh, Center for Cancer Research, Department of Biology, Massachusetts Institute of Technology, 40 Ames St., Cambridge, MA 02139. Phone: 617-253-0520; FAX: 617-253-9891; E-mail: ploegh{at}mit.edu

1 Abbreviations used in this paper: Cat B, cathepsin B; Cat D, cathepsin D; Cat S, cathepsin S; CLIP, class II–associated invariant chain peptides; ER, endoplasmic reticulum; Ii, invariant chain; LHVS, N-morpholinurea leucine–homophenylalanine–vinylsulfone–phenyl; LIP, leupeptin-induced polypeptide.


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