Invariant chain controls the activity of extracellular cathepsin L.
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.
Fiebiger
Edda
E
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
Maehr
René
R
Villadangos
José
J
Weber
Ekkehard
E
Erickson
Ann
A
Bikoff
Elizabeth
E
Ploegh
Hidde L
HL
Lennon-Duménil
Ana-Maria
AM
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
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