The protease inhibitor, N-acetyl-L-leucyl-L-leucyl-leucyl-L-norleucinal, decreases the pool of major histocompatibility complex class I-binding peptides and inhibits peptide trimming in the endoplasmic reticulum.
N-acetyl-L-leucyl-L-leucyl-L-norleucinal, (LLnL), which inhibits proteasomes in addition to other proteases, was found to prolong the association of major histocompatibility complex class I molecules with the transporters associated with antigen processing (TAP), and to slow their transport out of the endoplasmic reticulum (ER). LLnL induced a reversible accumulation of ubiquitinated proteins and changed the spectrum of peptides bound by class I molecules. These effects can probably be attributed to proteasome inhibition. Unexpectedly, in the TAP-deficient cell line .174, the rate of intracellular transport of human histocompatibility leukocyte antigen (HLA) A2 was also reduced by LLnL, and the generation of most HLA-A2-associated signal sequence peptides was inhibited. The inhibition of HLA-A2 transport in .174 cells was found to be less sensitive to LLnL than in wild-type cells, and a similar difference was found for a second protease inhibitor, benzyloxycarbonyl-L-leucyl-L-leucyl-L-phenylalanilal. These data suggest that under some conditions such inhibitors can block trimming of peptides by an ER peptidase in addition to inhibiting cytosolic peptide generation.
Hughes
E A
EA
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Ortmann
B
B
Surman
M
M
Cresswell
P
P
D000595:Amino Acid Sequence; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism; D002451:Cell Compartmentation; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding
D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D015395:Histocompatibility Antigens Class I; D007976:Leupeptins; D009842:Oligopeptides; D010455:Peptides; C063261:acetylleucyl-leucyl-norleucinal; C077180:N-benzyloxycarbonyl-leucyl-leucyl-phenylalaninal