The function of the proteasome system in MHC class I antigen processing

Stoltze, Lars; Nussbaum, Alexander K.; Sijts, Alice J.A.M.; Emmerich, Niels; Kloetzel, Peter‐M.; Schild, Hansjörg

doi:10.1016/s0167-5699(00)01665-0

Cited by 45 publications

(22 citation statements)

References 9 publications

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“…Candidates for these downstream proteases are THIMET, Tricorn, Multicorn, TPPII, and leucine aminopeptidase (26, 331,412,429,484). Some of the peptides that are generated by the proteasome can be transported through the ER to be presented to the immune system by the MHC class I molecules (306,424).…”

Section: Proteolysismentioning

confidence: 99%

“…Because peptides are anchored in the MHC I groove preferentially by hydrophobic terminal residues, immunoproteasomes could be instrumental in the generation of antigens for MHC I presentation (306,424). Indeed, the 26S proteasome can specifically hydrolyze a protein to yield a known MHC class I antigenic peptide (28), and inhibition of the proteasome blocks presentation of antigenic epitopes (53).…”

Section: Proteolysis and Antigen Presentationmentioning

confidence: 99%

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The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Glickman

Ciechanover

2002

Physiological Reviews

3,715

3,031

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Between the 1960s and 1980s, most life scientists focused their attention on studies of nucleic acids and the translation of the coded information. Protein degradation was a neglected area, considered to be a nonspecific, dead-end process. Although it was known that proteins do turn over, the large extent and high specificity of the process, whereby distinct proteins have half-lives that range from a few minutes to several days, was not appreciated. The discovery of the lysosome by Christian de Duve did not significantly change this view, because it became clear that this organelle is involved mostly in the degradation of extracellular proteins, and their proteases cannot be substrate specific. The discovery of the complex cascade of the ubiquitin pathway revolutionized the field. It is clear now that degradation of cellular proteins is a highly complex, temporally controlled, and tightly regulated process that plays major roles in a variety of basic pathways during cell life and death as well as in health and disease. With the multitude of substrates targeted and the myriad processes involved, it is not surprising that aberrations in the pathway are implicated in the pathogenesis of many diseases, certain malignancies, and neurodegeneration among them. Degradation of a protein via the ubiquitin/proteasome pathway involves two successive steps: 1) conjugation of multiple ubiquitin moieties to the substrate and 2) degradation of the tagged protein by the downstream 26S proteasome complex. Despite intensive research, the unknown still exceeds what we currently know on intracellular protein degradation, and major key questions have remained unsolved. Among these are the modes of specific and timed recognition for the degradation of the many substrates and the mechanisms that underlie aberrations in the system that lead to pathogenesis of diseases.

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Section: Proteolysismentioning

confidence: 99%

Section: Proteolysis and Antigen Presentationmentioning

confidence: 99%

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Glickman

Ciechanover

2002

Physiological Reviews

3,715

3,031

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“…The proteasome, an ATP-dependent, multi-subunit protease, plays the central role in intracellular protein degradation (Stoltze et al 2000a;Kloetzel 2001;Yewdell and Bennink 2001). After protein substrates have been degraded, the resulting peptide fragments are translocated from the cytoplasm to the endoplasmic reticulum and then loaded onto major histocompatibility complex (MHC) class I molecules (Rock and Goldberg 1999).…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

et al. 2003

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Intracellular proteins are degraded largely by proteasomes. In cells stimulated with gamma interferon , the active proteasome subunits are replaced by "immuno" subunits that form immunoproteasomes. Phylogenetic analysis of the immunosubunits has revealed that they evolve faster than their constitutive counterparts. This suggests that the immunoproteasome has evolved a function that differs from that of the constitutive proteasome. Accumulating experimental degradation data demonstrate, indeed, that the specificity of the immunoproteasome and the constitutive proteasome differs. However, it has not yet been quantified how different the specificity of two forms of the proteasome are. The main question, which still lacks direct evidence, is whether the immunoproteasome generates more MHC ligands. Here we use bioinformatics tools to quantify these differences and show that the immunoproteasome is a more specific enzyme than the constitutive proteasome. Additionally, we predict the degradation of pathogen proteomes and find that the immunoproteasome generates peptides that are better ligands for MHC binding than peptides generated by the constitutive proteasome. Thus, our analysis provides evidence that the immunoproteasome has co-evolved with the major histocompatibility complex to optimize antigen presentation in vertebrate cells.

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“…Efficient prediction of CTL epitopes from the PRAME tumor-associated protein was demonstrated using a combination of peptide-binding motifs and experimental digestion of long peptides by purified proteasome preparations [41]. Attempts are underway to define algorithms incorporating these new elements in the prediction process ( [42,43] and http://www.syfpeithi.de). Clearly, this type of approaches hold great promise to mine new tumor antigens from the human genome which can be expected to be completed in the foreseeable future [44].…”

Section: Approaches To the Molecular Identification Of Cytolytic T Lymentioning

confidence: 99%

T Cells in Tumor Immunity

Romero

Pittet²,

Zippelius³

et al. 2002

Cancer Immune Therapy

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The function of the proteasome system in MHC class I antigen processing

Cited by 45 publications

References 9 publications

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

T Cells in Tumor Immunity

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