Where are MHC-I molecules, like HLA-A and HLA-B, predominantly located within the cell?

MHC-I molecules, such as HLA-A and HLA-B, are predominantly located in the endoplasmic reticulum (ER). The synthesis of MHC-I occurs in the rough ER, where nascent peptides are loaded onto the MHC-I molecules. This process involves the assembly of the heavy chain and beta-2 microglobulin, followed by the binding of peptide fragments that are typically derived from endogenously synthesized proteins. After assembly and peptide loading, the MHC-I molecules are transported to the plasma membrane for presentation to CD8+ T cells.

The endoplasmic reticulum plays a critical role in ensuring that only properly folded MHC-I molecules with the correct bound peptides are expressed on the cell surface. This is crucial for the immune system's ability to detect and respond to intracellular pathogens and tumor cells.

Due to this fundamental role of the ER in the processing and assembly of MHC-I molecules, it is clear that this is the correct location for these structures prior to their transport to and expression on the plasma membrane.