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Ubiquitin and proteasomes

Antigen processing by the proteasome

Nature Reviews Molecular Cell Biology volume 2, pages 179–188 (2001)Cite this article

Key Points

  • Cells display intracellular antigens ? from both intracellular pathogens and self ? at the cell surface to distinguish between infected and unifected cells.

  • Each antigenic peptide is bound by an MHC class I molecule. MHC genes are highly polymorphic, with several hundred alleles. Each allele binds a unique set of peptides with an average length of 8?10 amino acids. The specificity of this interaction is mediated by anchor residues.

  • The proteasome is responsible for generating antigenic peptides, although in specific cases, other proteases might also contribute to the MHC class I peptide pool.

  • How does the proteasome gain access to cellular proteins? One prevalent view is that cellular proteins targeted for degradation are the main source of peptides. The defective ribosomal products model proposes that non-functional proteins are rapidly ubiquitylated and degraded by the proteasome as they are translated.

  • To process antigens more efficiently, the proteasome replaces some of its subunits to form an immunoproteasome. The cytokine interferon-γ induces these immunosubunits, which are cooperatively incorporated into the proteasome.

  • Formation of the immunoproteasome might result in subtle changes in the structure of the substrate?proteasome complex, which might in turn alter the peptide processing properties of the immunoproteasome.

  • Interferon-γ also induces the proteasome activator PA28, which leads to enhanced peptide presentation. PA28 is thought to facilitate peptide release from the proteasome by 'opening the gate' of the proteasome structure.

  • Some viral proteins interfere with the activity of the proteasome and reduce antigen presentation.

Abstract

The proteasome is an essential part of our immune surveillance mechanisms: by generating peptides from intracellular antigens it provides peptides that are then 'presented' to T cells. But proteasomes ? the waste-disposal units of the cell ? typically do not generate peptides for antigen presentation with high efficiency. How, then, does the proteasome adapt to serve the immune system well?

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Figure 1: Proteasome composition.
Figure 2: Antigen processing and presentation.
Figure 3: The DRiP model.
Figure 4: Formation of the immunoproteasome.
Figure 5: How immunoproteasomes affect peptide quality.
Figure 6: The proteasome gating mechanism.
Figure 7: How antigenic peptides achieve optimal binding to MHC class I proteins.

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Authors and Affiliations

  1. Institut für Biochemie, Medical Faculty, Charité, Humboldt University, Monbijoustrasse 2, Berlin, 10117 , Germany

    Peter-M. Kloetzel

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DATABASE LINKS

IFNγ

TAP

PA28

β1i

β5i

β2i

β1

β2

β5

hsc70

Ump1

PA28α

PA28β

crystal structure of the Saccharomyces cerevisiae 20S proteasome

X-ray structure analysis of mutant proteasomes

X-ray structure of PA28 bound to the 20S proteasome

FURTHER INFORMATION

IMGT/HLA sequence database

ENCYCLOPEDIA OF LIFE SCIENCES

Antigen processing

Histocompatibility antigens

Protease complexes

Ubiquitin pathway

Glossary

SELF

Endogenous peptides derived from the organism's own protein pool.

CYTOTOXIC T CELLS

T cells that can kill other cells. They are important in host defence against most viral pathogens.

MULTI-UBIQUITIN TAG

Ubiquitin is a small protein that can form multimeric chains. Multi-ubiquitin chains, which are covalently bound to a substrate, target this substrate to the 26S proteasome for degradation.

TRIPLE-A FAMILY

ATPases associated with a variety of cellular activities. They contain an ATP-binding site with two conserved motifs known as Walker A and Walker B.

CHAPERONE

Proteins that support the folding of other proteins.

AMINO-TERMINAL NUCLEOPHILE (NTN)-HYDROLASE

Enzyme family that shares an amino-terminal nucleophile as a single active-site residue, which can be threonine, serine or cysteine.

ANCHOR RESIDUE

Residues within an epitope that bind, via their side chains, into the pockets of the MHC molecule lining the peptide-binding groove of the MHC class I molecule.

HAPLOTYPE

A linked set of genes associated with the haploid genome. Mostly used in connection with genes of the MHC complex.

TRANSPORTER ASSOCIATED WITH ANTIGEN PROCESSING

(TAP). ATP-binding cassette protein involved in the transport of peptides from the cytosol to the endoplasmic reticulum.

CYTOKINES

Originally used to describe a group of immunomodulatory growth factors, the term cytokine is now used to describe a diverse group of soluble proteins that modulate the activities of cells and tissues.

COOPERATIVE

The incorporation of immunosubunits into the 20S proteasome is cooperative because the efficiency of their incorporation is strongly dependent on each other.

EPITOPE

A short peptide derived from a protein antigen. It binds to an MHC molecule (or an antibody) and is recognized by a specific T-cell clone (or B-cell clone).

CHLAMYDIA TRACHOMATIS

A Gram-negative bacterial pathogen.

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Kloetzel, PM. Antigen processing by the proteasome . Nat Rev Mol Cell Biol 2, 179–188 (2001). https://doi.org/10.1038/35056572

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