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Deletion of immunoproteasome subunits imprints on the transcriptome and has a broad impact on peptides presented by major histocompatibility complex I molecules.

ABSTRACT: Proteasome-mediated proteolysis plays a crucial role in many basic cellular processes. In addition to constitutive proteasomes (CPs), which are found in all eukaryotes, jawed vertebrates also express immunoproteasomes (IPs). Evidence suggests that the key role of IPs may hinge on their impact on the repertoire of peptides associated to major histocompatibility complex (MHC) I molecules. Using a label-free quantitative proteomics approach, we identified 417 peptides presented by MHC I molecules on primary mouse dendritic cells (DCs). By comparing MHC I-associated peptides (MIPs) eluted from primary DCs and thymocytes, we found that the MIP repertoire concealed a cell type-specific signature correlating with cell function. Notably, mass spectrometry analyses of DCs expressing or not IP subunits MECL1 and LMP7 showed that IPs substantially increase the abundance and diversity of MIPs. Bioinformatic analyses provided evidence that proteasomes harboring LMP7 and MECL1 have specific cleavage preferences and recognize unstructured protein regions. Moreover, while differences in MIP repertoire cannot be attributed to potential effects of IPs on gene transcription, IP subunits deficiency altered mRNA levels of a set of genes controlling DC function. Regulated genes segregated in clusters that were enriched in chromosomes 4 and 8. Our peptidomic studies performed on untransfected primary cells provide a detailed account of the MHC I-associated immune self. This work uncovers the dramatic impact of IP subunits MECL1 and LMP7 on the MIP repertoire and their non-redundant influence on expression of immune-related genes.

SUBMITTER: de Verteuil D

PROVIDER: S-EPMC2938112 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Deletion of immunoproteasome subunits imprints on the transcriptome and has a broad impact on peptides presented by major histocompatibility complex I molecules.

de Verteuil Danielle D Muratore-Schroeder Tara L TL Granados Diana P DP Fortier Marie-Hélène MH Hardy Marie-Pierre MP Bramoullé Alexandre A Caron Etienne E Vincent Krystel K Mader Sylvie S Lemieux Sébastien S Thibault Pierre P Perreault Claude C

Molecular & cellular proteomics : MCP 20100519 9

Proteasome-mediated proteolysis plays a crucial role in many basic cellular processes. In addition to constitutive proteasomes (CPs), which are found in all eukaryotes, jawed vertebrates also express immunoproteasomes (IPs). Evidence suggests that the key role of IPs may hinge on their impact on the repertoire of peptides associated to major histocompatibility complex (MHC) I molecules. Using a label-free quantitative proteomics approach, we identified 417 peptides presented by MHC I molecules o ...[more]

PMID: 20484733

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Project description:Rabbits are pivotal domestic animals for both the economy and as an animal model for human diseases. A large number of rabbits have been infected by rabbit hemorrhagic disease virus (RHDV) in natural and artificial pandemics in the past. Differences in presentation of antigenic peptides by polymorphic major histocompatibility complex (MHC) molecules to T-cell receptors (TCR) on T lymphocytes are associated with viral clearance in mammals. Here, we screened and identified a series of peptides derived from RHDV binding to the rabbit MHC class I molecule, RLA-A1. The small, hydrophobic B and F pockets of RLA-A1 capture a peptide motif analogous to that recognized by human class I molecule HLA-A*0201, with more restricted aliphatic anchors at P2 and PΩ positions. Moreover, the rabbit molecule is characterized by an uncommon residue combination of Gly53, Val55, and Glu56, making the 310 helix and the loop between the 310 and α1 helices closer to the α2 helix. A wider A pocket in RLA-A1 can induce a special conformation of the P1 anchor and may play a pivotal role in peptide assembly and TCR recognition. Our study broadens the knowledge of T-cell immunity in domestic animals and also provides useful insights for vaccine development to prevent infectious diseases in rabbits.IMPORTANCE We screened rabbit MHC class I RLA-A1-restricted peptides from the capsid protein VP60 of rabbit hemorrhagic disease virus (RHDV) and determined the structures of RLA-A1 complexed with three peptides, VP60-1, VP60-2, and VP60-10. From the structures, we found that the peptide binding motifs of RLA-A1 are extremely constraining. Thus, there is a generally restricted peptide selection for RLA-A1 compared to that for human HLA-A*0201. In addition, uncommon residues Gly53, Val55, and Glu56 of RLA-A1 are located between the 310 helix and α1 helix, which makes the steric position of the 310 helix in RLA-A1 much closer to the α2 helix than that found in other mammalian MHC class I molecules. This special conformation between the 310 helix and α1 helix plays a pivotal role in rabbit MHC class I assembly. Our results provide new insights into MHC class I molecule assembly and peptide presentation of domestic mammals. Furthermore, these data also broaden our knowledge on T-cell immunity in rabbits and may also provide useful information for vaccine development to prevent infectious diseases in rabbits.

Dataset Information

Deletion of immunoproteasome subunits imprints on the transcriptome and has a broad impact on peptides presented by major histocompatibility complex I molecules.

Publications

Deletion of immunoproteasome subunits imprints on the transcriptome and has a broad impact on peptides presented by major histocompatibility complex I molecules.

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