MHC class I molecules present peptide fragments mostly from nuclear and cytosolic antigens. Although the process is reasonably well characterized, the origin and whereabouts of the peptides has only recently become clear.
The latest additions to the scheme are peptidases. Various cytosolic aminopeptidases and an endoplasmic reticulum (ER) aminopeptidase have been defined. The half-life of peptides (∼5 seconds) in living cells has been determined.
Peptides can be derived not only from old proteins, but also from the same proteins that are degraded almost immediately after generation. This can be the result of defects in translation, folding or assembly, and the products are collectively known as defective ribosomal products (DRiPs). DRiPs are important to allow a rapid CD8+ T-cell response after infection.
Contrary to intuition, the process of antigen processing and presentation is inefficient. Potential antigens are destroyed at various levels including the proteasome, cytosolic peptidases and ER peptidases. The result of these processes is that only about one peptide out of every 10,000 proteins degraded will be presented by MHC class I molecules.
Many estimates have been made for the activities of the different steps in MHC class-I-antigen presentation. These numbers explain the inefficiency of MHC class-I-antigen presentation.
The inefficiency of antigen presentation sets a threshold on the minimum number of protein copies expressed for recognition by CD8+ T cells.
MHC class I molecules bind short peptides and present them to CD8+ T cells. Contrary to textbook descriptions, the generation of MHC class-I-associated peptides from endogenous proteins is a highly dynamic and remarkably inefficient process. Here, we describe recent experiments that show how nascent and mature proteins are degraded into peptides that are trimmed, transported and trimmed again to enable presentation of a small portion of the generated peptides. By linking the failure rate of protein synthesis with antigen presentation, a rapid T-cell response is ensured, which is crucial in combating viral infections. Presentation on MHC class I molecules is achieved by less than 0.1% of the specific peptides that have survived intracellular destruction. The other peptides are converted into free amino acids that are used for recycling into new proteins.
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We thank C. Sanders at Vanderbilt University for providing examples of inefficient protein biogenesis. This work was supported by the Dutch Cancer Society KWF.
The authors declare no competing financial interests.
Cartoon 1 | MHC class I antigen presentation: the basics. Intracellular proteins are degraded by the proteasome into peptides. The transporter for antigen processing (TAP) then translocates peptides into the lumen of the endoplasmic reticulum (ER). Newly synthesized MHC class I molecules require peptide binding for release from the ER and transport to the plasma membrane, where the peptide is presented to the immune system. (JPG 72 kb)
Cartoon 2 | The perils of protein biogenesis. All proteins are made by the ribosome using messenger RNA as a template. Nascent proteins are frequently stabilized by heat-shock proteins (HSPs), which probably facilitate correct folding and prevent aggregation. Despite this, a marked fraction of translation products is defective, resulting in incorrect (mistranslated or prematurely stopped), misfolded or misassembled proteins. These defective ribosomal products (DRiPs) are shunted to the proteasome for degradation, coupling protein production to MHC class I antigen presentation and enable a rapid T-cell response to new viral proteins. (JPG 84 kb)
Cartoon 3 | Complexities of MHC class I antigen presentation. Both defective ribosomal products (DRiPs) and mature proteins (retirees) are degraded by proteasomes, usually after polyubiquitylation. The proteasome digests proteins into peptides of various lengths. Many peptides are too small for presentation by MHC class I molecules and are recycled into amino acids that can be used for new proteins. Another fraction is appropriate or too long for MHC class I molecules. These, too, are substrates for various cytosolic peptidases that will degrade most to amino acids. Only a few (trimmed) peptides diffuse into the transporter for antigen processing (TAP). TAP translocates peptides into the lumen of the endoplasmic reticulum (ER), where they can associate with MHC class I molecules before or after trimming by ER aminopeptidases (ERAP). Peptides that fail to bind to MHC class I molecules are removed by the translocon SEC61 and enter the cytoplasm, where they will again be targets for the cytosolic peptidases. (JPG 137 kb)
- SIGNAL PEPTIDES
Targeting sequences in proteins that are required to send them to their subsequent destination. This could be the mitochondrion, nucleus, peroxisome or ER, endoplasmic reticulum, depending on amino-acid sequence and positioning in the protein. Signal sequences for ER targeting enter the ER lumen, are cleaved off, and can end up as an MHC class-I-binding peptide.
This endoplasmic-reticulum-resident aminopeptidase trims peptides to the size that is suitable for binding to MHC class I molecules. As both the proteasome and transporter for antigen processing handle peptides that are longer than those that bind to MHC class I molecules, either cytosolic peptidases and/or ERAP1 are required for correct epitope generation.
- SEC61 TRANSLOCON
An endoplasmic reticulum (ER) complex used by the ribosome to transfer nascent proteins into the ER lumen during translation. The same complex is also used to remove ER proteins and peptides, for transfer in the ER and degradation by the proteasome and peptidases, respectively.
Initiation of a CD8+ T-cell response to an antigen that is not present in antigen-presenting cells (APCs). The antigen must be taken up by APCs and then re-routed to the MHC class-I-presentation pathway.
- DEFECTIVE RIBOSOMAL PRODUCTS
(DRiPs). DRiPs include all proteins that are degraded by the proteasome before becoming functional. This could be the result of defects in transcription, splicing, translation, assembly or folding. DRiPs link antigen generation to presentation and ensure rapid CD8+ T-cell responses to infections.
- F-BOX PROTEINS
The target-recognizing subunit of the SCF (SKP1–cullin–F-box) complex. About 70 different F-box proteins are encoded in the human genome, most with unknown substrate specificity. After recognition by the F-box protein, E2 ubiquitin ligase transfers the first ubiquitin tag to the target protein, thereby initiating poly-ubiquitylation and ultimately degradation by the proteasome.
- FLUORESCENCE LOSS IN PHOTOBLEACHING
(FLIP). FLIP is the reverse of FRAP (fluorescence recovery after photobleaching) and is a microscopy technique used to follow the dynamics of fluorescent molecules in living cells. By bleaching fluorescence at one site in a cell, the redistribution of fluorescence to other sites illustrates the dynamics of the fluorescent probes.
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Yewdell, J., Reits, E. & Neefjes, J. Making sense of mass destruction: quantitating MHC class I antigen presentation. Nat Rev Immunol 3, 952–961 (2003). https://doi.org/10.1038/nri1250
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