Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 191, Issue 7, Pages 1177-1185Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.191.7.1177
Keywords
cysteine protease; antigen presentation; protease inhibitor; proteolysis; antigen presenting cell
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Funding
- NHLBI NIH HHS [HL48716, R01 HL060942, HL60942] Funding Source: Medline
- NIAID NIH HHS [K08AI01555] Funding Source: Medline
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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 similar to 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 ill 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 Il-MHC class II complexes, whereas cathepsin F was as efficient as cathepsin S ill 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.
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