MHC Class I Antigen Presentation Pathway

Core Idea

MHC Class I presents peptides derived from cytosolic proteins, primarily through the proteasomal-ER pathway. Cytosolic proteins are ubiquitinated and degraded by the 26S proteasome; peptides are transported to the ER by TAP, trimmed to 8-10 residues, and loaded onto MHC-I in the ER with chaperone assistance. Peptide-MHC-I complexes traffic through the Golgi to the cell surface where they signal CD8+ T cells.

How It's Best Learned

Follow a viral protein through ubiquitination, proteasomal cleavage, TAP transport, peptide trimming, and MHC-I loading. Compare this with ER-resident protein processing.

Common Misconceptions

• All peptides reach the ER through TAP (some are generated in the ER itself or transported back across the membrane). - MHC-I loading occurs in the cytoplasm (loading occurs in the ER-Golgi intermediate compartment).

Explainer

From your study of the major histocompatibility complex and antigen processing, you know that MHC molecules display peptide fragments on the cell surface so T cells can survey what is happening inside cells. MHC class I is expressed on virtually all nucleated cells, and its job is to present a sample of the cell's internal protein content to CD8+ cytotoxic T cells. If a cell is infected by a virus or has become cancerous, fragments of viral or abnormal proteins will appear in MHC-I, flagging the cell for destruction. The MHC-I presentation pathway is essentially an internal surveillance system: it takes proteins made in the cytosol, chops them into short peptides, and displays them on the cell surface for immune inspection.

The pathway begins in the cytoplasm with protein turnover. Cells constantly degrade old, misfolded, or defective proteins by tagging them with ubiquitin chains and feeding them into the 26S proteasome, a barrel-shaped protease complex. The proteasome cleaves proteins into peptide fragments, typically 8–15 amino acids long. During an immune response, cells upregulate a specialized version called the immunoproteasome, which has altered cleavage preferences that favor peptides with hydrophobic or basic C-terminal residues — exactly the anchor residues preferred by most MHC-I molecules. This is not coincidental; the proteasome and MHC-I have co-evolved to optimize antigen presentation.

The peptides generated in the cytosol must cross the ER membrane to reach MHC-I molecules, which are assembled and loaded inside the ER. This transport is performed by the transporter associated with antigen processing (TAP), a heterodimeric ABC transporter (TAP1/TAP2) embedded in the ER membrane. TAP preferentially transports peptides of 8–16 residues with hydrophobic C-termini — again matching MHC-I binding preferences. Once inside the ER lumen, peptides that are slightly too long are trimmed to the optimal 8–10 residues by ERAP (ER aminopeptidase). Meanwhile, newly synthesized MHC-I heavy chains are held in a peptide-loading complex consisting of the chaperones calnexin, calreticulin, ERp57, and most importantly tapasin, which bridges MHC-I to TAP, ensuring that MHC-I molecules are positioned right at the mouth of the transporter to receive incoming peptides.

When a peptide of appropriate length and anchor residues binds in the MHC-I groove, the complex stabilizes, the chaperones release, and the peptide-MHC-I complex travels through the Golgi to the cell surface. Complexes that fail to bind a suitable peptide are unstable and recycled. At the surface, CD8+ T cells scan these complexes using their T cell receptor. If a T cell recognizes a foreign peptide — say, a fragment of a viral coat protein — it will kill the presenting cell. This is why viruses like herpes and cytomegalovirus have evolved mechanisms to block TAP or downregulate MHC-I: evading this pathway lets them hide from CD8+ surveillance.