A. Craiu et al., 2 DISTINCT PROTEOLYTIC PROCESSES IN THE GENERATION OF A MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I-PRESENTED PEPTIDE, Proceedings of the National Academy of Sciences of the United Statesof America, 94(20), 1997, pp. 10850-10855
Although cellular proteins degraded by proteasomes are the source of m
ost antigenic peptides presented on major histocompatibility complex c
lass I molecules, it is unknown whether the eight-to nine-residue pept
ides that fit in the binding groove of class I molecules are directly
produced by proteasomes alone in vivo, If the eight-residue peptide SI
INFEKL from chicken ovalbumin is extended by one or several residues a
t its C terminus and microinjected into cells or expressed from a mini
gene, it is processed and presented on major histocompatibility comple
x class I, However, processing and presentation are inhibited by prote
asome inhibitors, such as lactacystin, In contrast, when SIINFEKL is e
xtended by 2 to 25 residues at its N terminus, its presentation is not
blocked by proteasome inhibitors, N-terminal processing also can occu
r when the extended peptide is cotranslationally inserted into the end
oplasmic reticulum. Thus, two different proteolytic steps in the gener
ation of an chicken ovalbumin-presented peptide can be distinguished.
Cleavage by the proteasome defines the proper C terminus, whereas dist
inct peptidase(s) in the cytosol or endoplasmic reticulum may generate
the appropriate N terminus from extended peptides.