Ubiquitination regulates MHC class II-peptide complex retention and degradation in dendritic cells.
The expression and turnover of MHC class II-peptide complexes (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to activate CD4 T cells efficiently. The half-life of surface pMHC-II is significantly greater in activated (mature) DCs than in resting (immature) DCs, but the molecular mechanism leading to this difference remains unknown. We now show that ubiquitination of pMHC-II by the E3 ubiquitin ligase membrane-associated RING-CH 1 (March-I) regulates surface expression, intracellular distribution, and survival of pMHC-II in DCs. DCs isolated from March-I-KO mice express very high levels of pMHC-II on the plasma membrane even before DC activation. Although ubiquitination does not affect the kinetics of pMHC-II endocytosis from the surface of DCs, the survival of pMHC-II is enhanced in DCs obtained from March-I-deficient and MHC-II ubiquitination-mutant mice. Using pMHC-II-specific mAb, we show that immature DCs generate large amounts of pMHC-II that are remarkably stable under conditions in which pMHC-II ubiquitination is blocked. Thus, the cellular distribution and stability of surface pMHC-II in DCs is regulated by ubiquitin-dependent degradation of internalized pMHC-II.
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Even
E
Walseng
Kazuyuki
K
Furuta
Berta
B
Bosch
Karis A
KA
Weih
Yohei
Y
Matsuki
Oddmund
O
Bakke
Satoshi
S
Ishido
Paul A
PA
Roche
D000818:Animals; D000911:Antibodies, Monoclonal; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II; C545340:MARCH1 protein, mouse; D044767:Ubiquitin-Protein Ligases