PMID- 26610428
OWN - NLM
STAT- MEDLINE
DCOM- 20160922
LR  - 20181113
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 5
DP  - 2015 Nov 27
TI  - pH-susceptibility of HLA-DO tunes DO/DM ratios to regulate HLA-DM catalytic 
      activity.
PG  - 17333
LID - 10.1038/srep17333 [doi]
LID - 17333
AB  - The peptide-exchange catalyst, HLA-DM, and its inhibitor, HLA-DO control 
      endosomal generation of peptide/class II major histocompatibility protein 
      (MHC-II) complexes; these complexes traffic to the cell surface for inspection by 
      CD4+ T cells. Some evidence suggests that pH influences DO regulation of DM 
      function, but pH also affects the stability of polymorphic MHC-II proteins, 
      spontaneous peptide loading, DM/MHC-II interactions and DM catalytic activity, 
      imposing challenges on approaches to determine pH effects on DM-DO function and 
      their mechanistic basis. Using optimized biochemical methods, we dissected 
      pH-dependence of spontaneous and DM-DO-mediated class II peptide exchange and 
      identified an MHC-II allele-independent relationship between pH, DO/DM ratio and 
      efficient peptide exchange. We demonstrate that active, free DM is generated from 
      DM-DO complexes at late endosomal/lysosomal pH due to irreversible, acid-promoted 
      DO destruction rather than DO/DM molecular dissociation. Any soluble DM that 
      remains in complex with DO stays inert. pH-exposure of DM-DO in cell lysates 
      corroborates such a pH-regulated mechanism, suggesting acid-activated generation 
      of functional DM in DO-expressing cells.
FAU - Jiang, Wei
AU  - Jiang W
AD  - Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
AD  - Stanford Program in Immunology, Stanford University, Stanford, CA 94305, USA.
FAU - Strohman, Michael J
AU  - Strohman MJ
AD  - Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
AD  - Stanford Program in Immunology, Stanford University, Stanford, CA 94305, USA.
FAU - Somasundaram, Sriram
AU  - Somasundaram S
AD  - Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
FAU - Ayyangar, Sashi
AU  - Ayyangar S
AD  - Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
FAU - Hou, Tieying
AU  - Hou T
AD  - Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
FAU - Wang, Nan
AU  - Wang N
AD  - Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
FAU - Mellins, Elizabeth D
AU  - Mellins ED
AD  - Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
AD  - Stanford Program in Immunology, Stanford University, Stanford, CA 94305, USA.
LA  - eng
GR  - 1F32A1089080/PHS HHS/United States
GR  - T32 AI007290/AI/NIAID NIH HHS/United States
GR  - T32 AI07290/AI/NIAID NIH HHS/United States
GR  - AI095813/AI/NIAID NIH HHS/United States
GR  - AI075253/AI/NIAID NIH HHS/United States
GR  - R21 AI095813/AI/NIAID NIH HHS/United States
GR  - UL1 RR025744/RR/NCRR NIH HHS/United States
GR  - UL1 TR001085/TR/NCATS NIH HHS/United States
GR  - R21 AI075253/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 - 20151127
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (HLA-D Antigens)
RN  - 0 (HLA-DM antigens)
RN  - 0 (HLA-DO antigens)
RN  - 0 (Peptides)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - Amino Acid Sequence
MH  - *Antigen Presentation
MH  - CD4-Positive T-Lymphocytes/cytology/immunology
MH  - Catalytic Domain
MH  - Dendritic Cells/cytology/immunology
MH  - Gene Expression/immunology
MH  - HLA-D Antigens/*chemistry/genetics/immunology
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Immunoassay
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Peptides/*chemistry/genetics/immunology
MH  - Recombinant Proteins/chemistry/genetics/immunology
PMC - PMC4661524
EDAT- 2015/11/28 06:00
MHDA- 2016/09/23 06:00
PMCR- 2015/11/27
CRDT- 2015/11/28 06:00
PHST- 2015/07/06 00:00 [received]
PHST- 2015/10/28 00:00 [accepted]
PHST- 2015/11/28 06:00 [entrez]
PHST- 2015/11/28 06:00 [pubmed]
PHST- 2016/09/23 06:00 [medline]
PHST- 2015/11/27 00:00 [pmc-release]
AID - srep17333 [pii]
AID - 10.1038/srep17333 [doi]
PST - epublish
SO  - Sci Rep. 2015 Nov 27;5:17333. doi: 10.1038/srep17333.