Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumors frequently display defects in the MHC-I antigen processing machinery, such as deficiency of the peptide transporter TAP. Interestingly, the residual peptide repertoire contains neo-antigens which are not presented by processing-proficient cells. We termed these immunogenic peptides TEIPP ('T-cell epitopes associated with impaired peptide processing') and were interested to unravel their TAP-independent processing pathways. With an array of chemical inhibitors we assessed the participation of numerous proteases to TAP-independent peptides and found that the previously described catalytic enzymes signal peptidase and furin contributed in a cell-type and MHC-I allele-specific way. In addition, a dominant role for the proteasome and metallopeptidases was observed. These findings raised the question how these proteasome products get access to MHC-I molecules. A novel TEIPP peptide-epitope that represented this intracellular route revealed that the lysosomal peptide transporter ABCB9 ('TAP-like') was dispensable for its presentation. Interestingly, prevention of endolysosomal vesicle acidification by bafilomycin enhanced the surface display of this TEIPP peptide, suggesting that this proteasome-dependent pathway intersects endolysosomes and that these antigens are merely destroyed there. In conclusion, the proteasome has a surprisingly dominant role in shaping the TAP-independent MHC-I peptide repertoire and some of these antigens might be targeted to the endocytic vesicular pathway.
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PMID:Dominant contribution of the proteasome and metalloproteinases to TAP-independent MHC-I peptide repertoire. 2498 5

Cross-presentation is thought to require transport of proteasome-generated peptides by the TAP transporters into MHC class I loading compartments for most antigens. However, a proteasome-dependent but TAP-independent pathway has also been described. Depletion of the pool of recycling cell surface MHC class I molecules available for loading with cross-presented peptides might partly or largely account for the critical role of TAP in cross-presentation of phagocytosed antigens. Here we examined a potential role of the homodimeric lysosomal TAP-like transporter in cross-presentation and in presentation of endogenous peptides by MHC class II molecules. We find that TAP-L is strongly recruited to dendritic cell phagosomes at a late stage, when internalized antigen and MHC class I molecules have been degraded or sorted away from phagosomes. Cross-presentation of a receptor-targeted antigen in vitro and of a phagocytosed antigen in vivo, as well as presentation of a cytosolic antigen by MHC class II molecules, is not affected by TAP-L deficiency. However, accumulation in vitro of a peptide optimally adapted to TAP-L selectivity in purified phagosomes is abolished by TAP-L deficiency. Unexpectedly, we find that TAP-L deficiency accelerates phagosome maturation, as reflected in increased Lamp2b recruitment and enhanced proteolytic degradation of phagocytosed antigen and in vitro transported peptides. Although additional experimentation will be required to definitely conclude on the role of TAP-L in transport of peptides presented by MHC class I and class II molecules, our data suggest that the principal role of TAP-L in dendritic cells may be related to regulation of phagosome maturation.
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PMID:Impact of the TAP-like transporter in antigen presentation and phagosome maturation. 2994 Dec 19