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Lysosomal Cysteine and Aspartic Proteases Are Heterogeneously Expressed and Act Redundantly to Initiate Human Invariant Chain Degradation¹

Cristina M. Costantino^*, Howard C. Hang^2,, Sally C. Kent^*, David A. Hafler^* and Hidde L. Ploegh^3,

^* Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and Whitehead Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142

Presentation of Ag by class II MHC is regulated by lysosomal proteases that not only destroy the class II invariant chain (Ii) chaperone but also generate the peptide Ag that is loaded onto the class II MHC dimer. We sought to determine the extent to which asparagine endopeptidase (AEP) influences human Ag and Ii processing. Our data confirm the constructive function of AEP in tetanus toxoid processing, but they are discordant with findings that suggest a destructive role for AEP in processing of the immunodominant myelin basic protein epitope. Furthermore, we observed no effect on invariant chain processing following AEP inhibition for several distinct allelic variants of human class II MHC products. We find that cysteine and aspartic proteases, as well as AEP, can act redundantly to initiate Ii processing. We detected considerable variation in lysosomal activity between different EBV-transformed B cell lines, but these differences do not result in altered regulation of invariant chain catabolism. We propose that, as for bound peptide Ag, the identity of the lysosomal enzyme that initiates invariant chain cleavage is dependent on the class II MHC allelic variants expressed.

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.

¹ This work was supported by National Institutes of Health grants and by the National Multiple Sclerosis Society. H.C.H. was supported by a Damon Runyon Cancer Research Foundation postdoctoral fellowship. S.C.K. was supported with a research grant from the Juvenile Diabetes Research Foundation International.

² Current address: Laboratory of Chemical Biology and Microbial Pathogenesis, Rockefeller University, New York, NY 10021.

³ Address correspondence and reprint requests to Dr. Hidde L. Ploegh, Whitehead Institute for Biomedical Research, Nine Cambridge Center, Room 361B, Cambridge, MA 02142. E-mail address: ploegh{at}wi.mit.edu

⁴ Abbreviations used in this paper: Ii, invariant chain; AEP, asparagine endopeptidase; AEPi, AEP inhibitor; AMC, 7-amido-4-methyl coumarin; CatB, cathepsin B (form also for cathepsins D, F, G, L, and S); LIP, leupeptin-induced peptide; MBP, myelin basic protein; MS, multiple sclerosis.