Article ; Online: Masking of a cathepsin G cleavage site in vivo contributes to the proteolytic resistance of major histocompatibility complex class II molecules.
2010 Volume 130, Issue 3, Page(s) 436–446
Abstract: Summary: The expression of major histocompatibility complex class II (MHC II) molecules is post ... Thus, in vivo, the CatG cleavage site is sterically inaccessible or masked by associated molecules ... A combination of intrinsic and context-dependent proteolytic resistance may allow peptide capture by MHC II ...
| Abstract | Summary: The expression of major histocompatibility complex class II (MHC II) molecules is post-translationally regulated by endocytic protein turnover. Here, we identified the serine protease cathepsin G (CatG) as an MHC II-degrading protease by in vitro screening and examined its role in MHC II turnover in vivo. CatG, uniquely among endocytic proteases tested, initiated cleavage of detergent-solubilized native and recombinant soluble MHC II molecules. CatG cleaved human leukocyte antigen (HLA)-DR isolated from both HLA-DM-expressing and DM-null cells. Even following CatG cleavage, peptide binding was retained by pre-loaded, soluble recombinant HLA-DR. MHC II cleavage occurred on the loop between fx1 and fx2 of the membrane-proximal beta2 domain. All allelic variants of HLA-DR tested and murine I-A(g7) class II molecules were susceptible, whereas murine I-E(k) and HLA-DM were not, consistent with their altered sequence at the P1' position of the CatG cleavage site. CatG effects were reduced on HLA-DR molecules with DRB mutations in the region implicated in interaction with HLA-DM. In contrast, addition of CatG to intact B-lymphoblastoid cell lines (B-LCLs) did not cause degradation of membrane-bound MHC II. Moreover, inhibition or genetic ablation of CatG in primary antigen-presenting cells did not cause accumulation of MHC II molecules. Thus, in vivo, the CatG cleavage site is sterically inaccessible or masked by associated molecules. A combination of intrinsic and context-dependent proteolytic resistance may allow peptide capture by MHC II molecules in harshly proteolytic endocytic compartments, as well as persistent antigen presentation in acute inflammatory settings with extracellular proteolysis. |
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| MeSH term(s) | Amino Acid Sequence ; Amino Acid Substitution ; Animals ; B-Lymphocytes/metabolism ; Cathepsin G/antagonists & inhibitors ; Cathepsin G/chemistry ; Cathepsin G/genetics ; Cathepsin G/metabolism ; Cathepsins/metabolism ; Cell Line ; Dendritic Cells/metabolism ; HLA-D Antigens/genetics ; HLA-D Antigens/metabolism ; HLA-DR Antigens/genetics ; HLA-DR Antigens/metabolism ; HLA-DR1 Antigen/genetics ; HLA-DR1 Antigen/metabolism ; HLA-DR3 Antigen/genetics ; HLA-DR3 Antigen/metabolism ; Hemagglutinin Glycoproteins, Influenza Virus/metabolism ; Histocompatibility Antigens Class II/genetics ; Histocompatibility Antigens Class II/metabolism ; Histocompatibility Antigens Class II/pharmacology ; Humans ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Models, Molecular ; Molecular Sequence Data ; Peptide Fragments/analysis ; Peptide Fragments/metabolism ; Peptides/metabolism ; Polymorphism, Genetic/genetics ; Protein Binding/physiology ; Protein Processing, Post-Translational ; Recombinant Proteins/metabolism ; Sequence Alignment |
| Chemical Substances | HLA-D Antigens ; HLA-DM antigens ; HLA-DR Antigens ; HLA-DR1 Antigen ; HLA-DR3 Antigen ; Hemagglutinin Glycoproteins, Influenza Virus ; Histocompatibility Antigens Class II ; I-E-antigen ; Peptide Fragments ; Peptides ; Recombinant Proteins ; influenza hemagglutinin (306-318) ; Cathepsins (EC 3.4.-) ; Cathepsin G (EC 3.4.21.20) |
| Language | English |
| Publishing date | 2010-03-17 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 80124-0 |
| ISSN | 1365-2567 ; 0019-2805 ; 0953-4954 |
| ISSN (online) | 1365-2567 |
| ISSN | 0019-2805 ; 0953-4954 |
| DOI | 10.1111/j.1365-2567.2010.03247.x |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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