title: Invariant chain controls the activity of extracellular cathepsin L.
abstract: 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 (p41(65aa)) 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 p41(65aa) with mature CatL allows extracellular accumulation of the active enzyme. We detected mature CatL as a complex with p41(65aa) 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 p41(65aa) is catalytically active as demonstrated by active site labeling and elastin degradation assays. We propose that p41(65aa) 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.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Edda
authors.initials: E
authors.lastname: Fiebiger
authors.forename: René
authors.initials: R
authors.lastname: Maehr
authors.forename: José
authors.initials: J
authors.lastname: Villadangos
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Weber
authors.forename: Ann
authors.initials: A
authors.lastname: Erickson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bikoff
authors.forename: Hidde L
authors.initials: HL
authors.lastname: Ploegh
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Lennon-Duménil
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000378:metabolism*; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D003470:Culture Media; D003546:Cysteine Endopeptidases; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015854:Up-Regulation
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D003470:Culture Media; D000949:Histocompatibility Antigens Class II; D008070:Lipopolysaccharides; C045084:invariant chain; D007371:Interferon-gamma; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D056668:Cathepsin L; C534278:Ctsl protein, mouse