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

Amit Tuli,Mahak Sharma,Haley L Capek,Naava Naslavsky,Steve Caplan,Joyce C Solheim

doi:10.1074/jbc.m109.039727

Abstract

Earlier studies have demonstrated interaction of the murine major histocompatibility complex (MHC) class I molecule K(d) with amyloid precursor-like protein 2 (APLP2), a ubiquitously expressed member of the amyloid precursor protein family. Our current findings indicate that APLP2 is internalized in a clathrin-dependent manner, as shown by utilization of inhibitors of the clathrin pathway. Furthermore, we demonstrated that APLP2 and K(d) bind at the cell surface and are internalized together. The APLP2 cytoplasmic tail contains two overlapping consensus motifs for binding to the adaptor protein-2 complex, and mutation of a tyrosine shared by both motifs severely impaired APLP2 internalization and ability to promote K(d) endocytosis. Upon increased expression of wild type APLP2, K(d) molecules were predominantly directed to the lysosomes rather than recycled to the plasma membrane. These findings suggest a model in which APLP2 binds K(d) at the plasma membrane, facilitates uptake of K(d) in a clathrin-dependent manner, and routes the endocytosed K(d) to the lysosomal degradation pathway. Thus, APLP2 has a multistep trafficking function that influences the expression of major histocompatibility complex class I molecules at the plasma membrane.

Highlights

The efficacy of the cellular immune response to intracellular pathogens and tumors is reliant on major histocompatibility complex (MHC)5 class I molecules
We have shown that Amyloid precursor-like protein 2 (APLP2) binds to human MHC class I molecules, and that increased APLP2 expression causes down-regulation of human MHC class I molecules at the plasma membrane [19]
Endocytosis of MHC class I molecules has been studied using several cell types as models, including lymphocytes, fibroblasts, and macrophages, with variability reported for the extent and pathway of internalization [35,36,37,38,39,40,41,42,43,44,45,46]

Summary

Introduction

The efficacy of the cellular immune response to intracellular pathogens and tumors is reliant on major histocompatibility complex (MHC)5 class I molecules. APLP2 mutated at this cytoplasmic domain tyrosine residue, in contrast to wild type APLP2, was unable to facilitate the endocytosis of Kd. Cells expressing a high level of APLP2 were noted to have relatively few internalized Kd molecules recycling to the plasma membrane, and delivery of Kd to the lysosomes in these cells was shown by inhibition of lysosomal function with ammonium chloride.

Results

Conclusion