Amyloid Precursor-Like Protein 2 Increases the Endocytosis, Instability, and Turnover of the H2-Kd MHC Class I Molecule

Abstract

The defense against the invasion of viruses and tumors relies on the presentation of viral and tumor-derived peptides to CTL by cell surface MHC class I molecules. Previously, we showed that the ubiquitously expressed protein amyloid precursor-like protein 2 (APLP2) associates with the folded form of the MHC class I molecule Kd. In the current study, APLP2 was found to associate with folded Kd molecules following their endocytosis and to increase the amount of endocytosed Kd. In addition, increased expression of APLP2 was shown to decrease Kd surface expression and thermostability. Correspondingly, Kd thermostability and surface expression were increased by down-regulation of APLP2 expression. Overall, these data suggest that APLP2 modulates the stability and endocytosis of Kd molecules.

Mechanism for Amyloid Precursor-like Protein 2 Enhancement of Major Histocompatibility Complex Class I Molecule Degradation

“…Although our previous studies demonstrated that APLP2 is bound to the endocytosed K d molecule, the specific location where the binding occurs was not identified (4). In the present study, we established that APLP2 binds K d at the cell surface before these two proteins internalize into the same endocytic vesicles.…”

“…Internalized Together-Previous studies from our laboratories showed that APLP2 co-localized in endosomes with K d internalized from the cell surface and that APLP2 could be co-immunoprecipitated with internalized K d (4). To determine whether the interaction between APLP2 and K d occurs at the cell surface, K d molecules at the surface of HeLa-etK d cells were labeled with the 34-1-2 Ab on ice for 20 min, and then the cells were lysed and Ab complexes isolated with Protein A-Sepharose.…”

“…APLP2 regulates the level of folded K d molecules at the cell surface: a reduction in APLP2 expression causes an elevation in the amount of folded K d at the plasma membrane, and an increase in APLP2 expression results in a decline in folded K d surface expression (3,4). Higher APLP2 expression lowers the level of K d at the plasma membrane by increasing the endocytosis, destabilization, and turnover of K d molecules (4).…”

“…APLP2 regulates the level of folded K d molecules at the cell surface: a reduction in APLP2 expression causes an elevation in the amount of folded K d at the plasma membrane, and an increase in APLP2 expression results in a decline in folded K d surface expression (3,4). Higher APLP2 expression lowers the level of K d at the plasma membrane by increasing the endocytosis, destabilization, and turnover of K d molecules (4). The family of proteins to which APLP2 belongs includes APL-1 in Caenorhabditis elegans, APPL in Drosophila, and three proteins in mammals: amyloid precursor protein (APP), amyloid precursor-like protein 1, and APLP2 (5,6).…”

Conserved Amino Acids within the Adenovirus 2 E3/19K Protein Differentially Affect Downregulation of MHC Class I and MICA/B Proteins

“…Although their critical importance for the interaction of E3/19K with HLA-I alleles not present in 293 cells cannot be excluded their conservation may imply an essential role for the interaction with other potential E3/19K target proteins. Interestingly, E3/19K was shown to increase complex formation of certain MHC-I alleles with the amyloid precursor-like protein 2, which has been implicated in peptide transfer (37,69) and in modulation of the stability and endocytosis of some murine and human MHC-I alleles (70,71).…”