Assembly and function of the two ABC transporter proteins encoded in the human major histocompatibility complex

Abstract

PRESENTATION of cytoplasmic antigens to class I-restricted cytotoxic T cells implied the existence of a specialized peptide transporter^1–3 (reviewed in ref. 4). For most class I heavy chains, association with peptides of the appropriate length is required for stable assembly with β ₂-microglobulin^5–11. Mutant cells RMA–S (ref. 12) and .174/T2 (refs 13,14) neither assemble stable class I molecules nor present intracellular antigens, and we have suggested that they have lost a function required for the transport of short peptides from the cytosol to the endoplasmic reticulum^5–7. The genetic defect in .174 has been localized to a large deletion in the class II region of the major histocompatibility complex^6,15,16, within which two genes (RING4 and RING11) have been identified that code for 'ABC' (ATP-binding cassette) transporters^15,17–21. We report here that the protein products of these two genes assemble to form a complex. Defects in either protein result in the formation of unstable class I molecules and loss of presentation of intracellular antigens. The molecular defect in a new mutant, BM36.1, is shown to be in the ATP-binding domain of the RING11/PSF2 protein. This is in contrast to the mutant .134 (ref. 15), which lacks the RING4/PSF1 protein.