N-acetyl-L-leucyl-L-leucyl-L-norleucinal (LLnL), which reversibly inhibits the 
proteasome in addition to other proteases, and a more specific irreversible 
inhibitor of the proteasome, lactacystin, were found to cause the accumulation 
of major histocompatibility complex (MHC) class I heavy chains in the cytosol of 
the beta2-microglobulin-deficient cell line Daudi and the TAP-deficient cell 
line .174. These cell lines, which are severely impaired in their ability to 
fold MHC class I heavy chain, showed an accumulation of soluble class I heavy 
chains at different rates over a period of hours in the presence of LLnL. The 
accumulation of soluble class I heavy chains in the presence of either LLnL or 
lactacystin was easily revealed in Daudi and .174 but almost undetectable in a 
Daudi transfectant expressing beta2-microglobulin and in 45.1, the wild-type 
parent of .174. The soluble class I heavy chain was also found to be devoid of 
its N-linked glycan and to be located in the cytosol. When the gene for ICP47, a 
herpes simplex virus protein that blocks the translocation of peptides into the 
endoplasmic reticulum, was transfected into 45.1, a similar accumulation of 
soluble MHC class I heavy chain was detectable. These data suggest that in cells 
where the MHC class I molecule is unable to assemble properly, the misfolded 
heavy chain is removed from the endoplasmic reticulum to the cytosol, 
deglycosylated, and degraded by the proteasome.