Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment - PubMed (original) (raw)
Misfolded major histocompatibility complex class I molecules accumulate in an expanded ER-Golgi intermediate compartment
G Raposo et al. J Cell Biol. 1995 Dec.
Abstract
Misfolded membrane proteins are rapidly degraded, often shortly after their synthesis and insertion in the endoplasmic reticulum (ER), but the exact location and mechanisms of breakdown remain unclear. We have exploited the requirement of MHC class I molecules for peptide to achieve their correct conformation: peptide can be withheld by introducing a null mutation for the MHC-encoded peptide transporter, TAP. By withholding TAP-dependent peptides, the vast majority of newly synthesized class I molecules fails to leave the endoplasmic reticulum and is degraded. We used mice transgenic for HLA-B27 on a TAP1-deficient background to allow visualization by immunoelectron microscopy of misfolded HLA-B27 molecules in thymic epithelial cells. In such HLA transgenic animals, the TAP mutation can be considered a genetic switch that allows control over the extent of folding of the protein of interest, HLA-B27, while the rate of synthesis of the constituent subunits remains unaltered. In TAP1-deficient, HLA-B27 transgenic animals, HLA-B27 molecules fail to assemble correctly, and do not undergo carbohydrate modifications associated with the Golgi apparatus, such as conversion to Endoglycosidase H resistance, and acquisition of sialic acids. We show that such molecules accumulate in an expanded network of tubular and fenestrated membranes. This compartment has its counterpart in normal thymic epithelial cells, and is identified as an ER-Golgi intermediate. We detect the presence of ubiquitin and ubiquitin-conjugating enzymes in association with this compartment, suggesting a nonlysosomal mode of degradation of its contents.
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