The Journal of Experimental Medicine
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Published 4 November 2002. doi:10.1084/jem.20020762
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© Rockefeller University Press, 0022-1007/2002/11/1263 $5.00
The Journal of Experimental Medicine, Volume 196, Number 9, 1263-1270

Brief Definitive Report

Invariant Chain Controls the Activity of Extracellular Cathepsin L

Edda Fiebiger1, René Maehr1, José Villadangos2, Ekkehard Weber3, Ann Erickson4, Elizabeth Bikoff5, Hidde L. Ploegh1 and Ana-Maria Lennon-Duménil1

1 Department of Pathology, Harvard Medical School, Boston, MA 02115
2 Department of Immunology, The Walter and Eliza Hall Institute, Melbourne, Victoria 350, Australia
3 Department of Physiological Chemistry, Martin-Luther-University Halle-Wittenberg, Halle 06097, Germany
4 Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599
5 Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138

Address correspondence to Hidde Ploegh, Department of Pathology, Harvard Medical School, Boston, MA 02115. Phone: 617-432-4776; Fax: 617-432-4775; E-mail: ploegh{at}hms.harvard.edu

Secretion of proteases is critical for degradation of the extracellular matrix during an inflammatory response. Cathepsin (Cat) S and L are the major elastinolytic cysteine proteases in mouse macrophages. A 65 amino acid segment of the p41 splice variant (p4165aa) of major histocompatibility complex class II–associated invariant chain (Ii) binds to the active site of CatL and permits the maintenance of a pool of mature enzyme in endosomal compartments of macro-phages and dendritic cells (DCs). Here we show that interaction of p4165aa with mature CatL allows extracellular accumulation of the active enzyme. We detected mature CatL as a complex with p4165aa in culture supernatants from antigen-presenting cells (APCs). Extracellular accumulation of mature CatL is up-regulated by inflammatory stimuli as observed in interferon (IFN)-{gamma}–treated macrophages and lipopolysaccharide (LPS)-activated DCs. Despite the neutral pH of the extracellular milieu, released CatL associated with p4165aa is catalytically active as demonstrated by active site labeling and elastin degradation assays. We propose that p4165aa stabilizes CatL in the extracellular environment and induces a local increase in the concentration of matrix-degrading enzymes during inflammation. Through its interaction with CatL, Ii may therefore control the migratory response of APCs and/or the recruitment of effectors of the inflammatory response.

Key Words: protease • invariant chain • secretion • antigen-presenting cells • extracellular matrix degradation


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