Supplementary information

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.

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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.

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