Pathways accessory to proteasomal proteolysis are less efficient in major histocompatibility complex class I antigen production.
Degradation of cytosolic proteins depends largely on the proteasome, and a fraction of the cleavage products are presented as major histocompatibility complex (MHC) class I-bound ligands at the cell surface of antigen presenting cells. Proteolytic pathways accessory to the proteasome contribute to protein turnover, and their up-regulation may complement the proteasome when proteasomal proteolysis is impaired. Here we show that reduced reliance on proteasomal proteolysis allowed a reduced efficiency of MHC class I ligand production, whereas protein turnover and cellular proliferation were maintained. Using the proteasomal inhibitor adamantane-acetyl-(6-aminohexanoyl)3-(leucinyl)3-vinyl-(methyl)-sulphone, we show that covalent inhibition of all three types of proteasomal beta-subunits (beta(1), beta(2), and beta(5)) was compatible with continued growth in cells that up-regulate accessory proteolytic pathways, which include cytosolic proteases as well as deubiquitinating enzymes. However, under these conditions, we observed poor assembly of H-2D(b) molecules and inhibited presentation of endogenous tumor antigens. Thus, the tight link between protein turnover and production of MHC class I ligands can be broken by enforcing the substitution of the proteasome with alternative proteolytic pathways.
Kessler
Benedikt
B
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hong
Xu
X
Petrovic
Jelena
J
Borodovsky
Anna
A
Dantuma
Nico P
NP
Bogyo
Matthew
M
Overkleeft
Herman S
HS
Ploegh
Hidde
H
Glas
Rickard
R
D000818:Animals; D017951:Antigen Presentation; D003546:Cysteine Endopeptidases / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D006183:H-2 Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D013450:Sulfones / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D025801:Ubiquitin / Q000378:metabolism
C423916:4-hydroxy-5-iodo-3-nitrophenylacetyl-leucyl-leucyl-leucinal-vinyl sulfone; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D015395:Histocompatibility Antigens Class I; D009097:Multienzyme Complexes; D009842:Oligopeptides; D013450:Sulfones; D025801:Ubiquitin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex