PMID- 20331476
OWN - NLM
STAT- MEDLINE
DCOM- 20100826
LR  - 20211028
IS  - 1365-2567 (Electronic)
IS  - 0019-2805 (Print)
IS  - 0019-2805 (Linking)
VI  - 130
IP  - 3
DP  - 2010 Jul
TI  - Masking of a cathepsin G cleavage site in vivo contributes to the proteolytic 
      resistance of major histocompatibility complex class II molecules.
PG  - 436-46
LID - 10.1111/j.1365-2567.2010.03247.x [doi]
AB  - 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.
FAU - Burster, Timo
AU  - Burster T
AD  - Division of Endocrinology and Diabetes, Department of Internal Medicine I, Ulm 
      University, Ulm, Germany. tburster@stanford.edu
FAU - Macmillan, Henriette
AU  - Macmillan H
FAU - Hou, Tieying
AU  - Hou T
FAU - Schilling, James
AU  - Schilling J
FAU - Truong, Phi
AU  - Truong P
FAU - Boehm, Bernhard O
AU  - Boehm BO
FAU - Zou, Fang
AU  - Zou F
FAU - Lau, Kenneth
AU  - Lau K
FAU - Strohman, Michael
AU  - Strohman M
FAU - Schaffert, Steven
AU  - Schaffert S
FAU - Busch, Robert
AU  - Busch R
FAU - Mellins, Elizabeth D
AU  - Mellins ED
LA  - eng
GR  - 18543/ARC_/Arthritis Research UK/United Kingdom
GR  - 18543/VAC_/Versus Arthritis/United Kingdom
GR  - T32 AI007290/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100317
PL  - England
TA  - Immunology
JT  - Immunology
JID - 0374672
RN  - 0 (HLA-D Antigens)
RN  - 0 (HLA-DM antigens)
RN  - 0 (HLA-DR Antigens)
RN  - 0 (HLA-DR1 Antigen)
RN  - 0 (HLA-DR3 Antigen)
RN  - 0 (Hemagglutinin Glycoproteins, Influenza Virus)
RN  - 0 (Histocompatibility Antigens Class II)
RN  - 0 (I-E-antigen)
RN  - 0 (Peptide Fragments)
RN  - 0 (Peptides)
RN  - 0 (Recombinant Proteins)
RN  - 0 (influenza hemagglutinin (306-318))
RN  - EC 3.4.- (Cathepsins)
RN  - EC 3.4.21.20 (Cathepsin G)
SB  - IM
EIN - Immunology. 2010 Nov;131(3):450
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - B-Lymphocytes/metabolism
MH  - Cathepsin G/antagonists & inhibitors/*chemistry/genetics/*metabolism
MH  - Cathepsins/metabolism
MH  - Cell Line
MH  - Dendritic Cells/metabolism
MH  - HLA-D Antigens/genetics/metabolism
MH  - HLA-DR Antigens/genetics/metabolism
MH  - HLA-DR1 Antigen/genetics/metabolism
MH  - HLA-DR3 Antigen/genetics/metabolism
MH  - Hemagglutinin Glycoproteins, Influenza Virus/metabolism
MH  - Histocompatibility Antigens Class II/genetics/*metabolism/pharmacology
MH  - Humans
MH  - Macrophages/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Peptide Fragments/analysis/metabolism
MH  - Peptides/metabolism
MH  - Polymorphism, Genetic/genetics
MH  - Protein Binding/physiology
MH  - *Protein Processing, Post-Translational
MH  - Recombinant Proteins/metabolism
MH  - Sequence Alignment
PMC - PMC2913223
EDAT- 2010/03/25 06:00
MHDA- 2010/08/27 06:00
PMCR- 2011/07/01
CRDT- 2010/03/25 06:00
PHST- 2010/03/25 06:00 [entrez]
PHST- 2010/03/25 06:00 [pubmed]
PHST- 2010/08/27 06:00 [medline]
PHST- 2011/07/01 00:00 [pmc-release]
AID - IMM3247 [pii]
AID - 10.1111/j.1365-2567.2010.03247.x [doi]
PST - ppublish
SO  - Immunology. 2010 Jul;130(3):436-46. doi: 10.1111/j.1365-2567.2010.03247.x. Epub 
      2010 Mar 17.