Abstract
Like ubiquitin (Ub), the ubiquitin-like protein FAT10 can serve as a signal for proteasome-dependent protein degradation. Here, we investigated the contribution of FAT10 substrate modification to MHC class I antigen presentation. We show that N-terminal modification of the human cytomegalovirus-derived pp65 antigen to FAT10 facilitates direct presentation and dendritic cell-mediated cross-presentation of the HLA-A2 restricted pp65495–503 epitope. Interestingly, our data indicate that the pp65 presentation initiated by either FAT10 or Ub partially relied on the 19S proteasome subunit Rpn10 (S5a). However, FAT10 distinguished itself from Ub in that it promoted a pp65 response which was not influenced by immunoproteasomes or PA28. Further divergence occurred at the level of Ub-binding proteins with NUB1 supporting the pp65 presentation arising from FAT10, while it exerted no effect on that initiated by Ub. Collectively, our data establish FAT10 modification as a distinct and alternative signal for facilitated MHC class I antigen presentation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-012-0933-5) contains supplementary material, which is available to authorized users.
Highlights
The production of minimal CD8? T cell antigenic peptides mostly depends on the degradation of target proteins by the ubiquitin–proteasome system (UPS)
Further divergence occurred at the level of Ub-binding proteins with NUB1 supporting the pp65 presentation arising from FAT10, while it exerted no effect on that initiated by Ub
Because both Ub and FAT10 serve as signals for proteasomedependent degradation, we compared their impact on MHC class I presentation
Summary
T cell antigenic peptides mostly depends on the degradation of target proteins by the ubiquitin–proteasome system (UPS). In this pathway, covalently attached ubiquitin (Ub) typically marks a substrate protein for degradation by the 26S proteasome, and it has been shown that increased susceptibility to ubiquitylation can facilitate MHC class I antigen presentation in vivo [1,2,3]. IFN-c stimulation is accompanied by increased expression of the proteasome activator PA28, which associates with the 20S proteasome, thereby forming so-called hybrid proteasomes complexes (i.e. 19S-20S-PA28) that enhance the production of antigenic peptides [10, 11]
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