Major histocompatibility class I folding, assembly, and degradation: a paradigm for two-stage quality control in the endoplasmic reticulum.

摘要

Protein folding in living cells is a complex process involving many interdependent factors. The primary site for folding of nascent proteins destined for secretion is the endoplasmic reticulum (ER). Several disease states, including cystic fibrosis, are brought about because of irregularities in protein folding. Under normal cellular conditions, "quality control" mechanisms ensure that only correctly folded proteins are exported from the ER, with incorrectly folded or incompletely assembled proteins being degraded. Quality control mechanisms can be divided into two broad processes: (1) Primary quality control involves general mechanisms that are not specific for individual proteins; these monitor the fidelity of nascent protein folding in the ER and mediate the destruction of incompletely folded proteins. (2) Partially folded or assembled proteins may be subject to secondary quality control mechanisms that are protein- or protein-family-specific. Here we use the folding and assembly of major histocompatibility complex (MHC) class I as an example to illustrate the processes of quality control in the ER. MHC class I, a trimeric complex assembled in the ER of virally infected or malignant cells, presents antigenic peptide to cytotoxic T lymphocytes; this mediates cell killing and thereby prevents the spread of infection or malignancy. The folding and assembly of MHC class I is subjected to both primary and secondary quality control mechanisms that lead either to correct folding, assembly, and secretion or to degradation via a proteasome-associated mechanism.