Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages.
The major histocompatibility complex (MHC) class II-associated invariant chain (Ii) regulates intracellular trafficking and peptide loading of MHC class II molecules. Such loading occurs after endosomal degradation of the invariant chain to a approximately 3-kD peptide termed CLIP (class II-associated invariant chain peptide). Cathepsins L and S have both been implicated in degradation of Ii to CLIP in thymus and peripheral lymphoid organs, respectively. However, macrophages from mice deficient in both cathepsins S and L can process Ii and load peptides onto MHC class II dimers normally. Both processes are blocked by a cysteine protease inhibitor, indicating the involvement of an additional Ii-processing enzyme(s). Comparison of cysteine proteases expressed by macrophages with those found in splenocytes and dendritic cells revealed two enzymes expressed exclusively in macrophages, cathepsins Z and F. Recombinant cathepsin Z did not generate CLIP from Ii-MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S in CLIP generation. Inhibition of cathepsin F activity and MHC class II peptide loading by macrophages exhibited similar specificity and activity profiles. These experiments show that cathepsin F, in a subset of antigen presenting cells (APCs), can efficiently degrade Ii. Different APCs can thus use distinct proteases to mediate MHC class II maturation and peptide loading.
Shi
G P
GP
Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bryant
R A
RA
Riese
R
R
Verhelst
S
S
Driessen
C
C
Li
Z
Z
Bromme
D
D
Ploegh
H L
HL
Chapman
H A
HA
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D056646:Cathepsin F; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D006224:Cricetinae; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D010450:Endopeptidases; D015870:Gene Expression; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016676:Macrophages, Alveolar / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000276:immunology; D013450:Sulfones / Q000494:pharmacology
D000944:Antigens, Differentiation, B-Lymphocyte; D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D000949:Histocompatibility Antigens Class II; C404948:JPM 565; D010455:Peptides; D013450:Sulfones; C045084:invariant chain; C115125:morpholin- urea-phenylalanyl-homophenylalanyl-vinylsulfone-phenyl; D007073:Immunoglobulin E; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S; C534090:CTSF protein, human; D056646:Cathepsin F; C534092:Ctsf protein, mouse; D007930:Leucine