Amyloid precursor-like protein 2 association with HLA class I molecules

Tuli, Amit; Sharma, Mahak; Wang, Xiaojian; Simone, Laura; Capek, Haley L.; Cate, Steven; Hildebrand, William H.; Naslavsky, Naava; Caplan, Steve; Solheim, Joyce C.

doi:10.1007/s00262-009-0657-z

Cited by 18 publications

(38 citation statements)

References 51 publications

(62 reference statements)

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“…Therefore, the effects of increased APLP2 on MHC class I molecules that we have demonstrated have possible implications not only in normal MHC class I molecule turnover but also in cancer evasion of the cellular immune response. Recent findings from our laboratory indicating that APLP2 is highly expressed in many human tumor cell lines and decreases the cell surface expression of human MHC class I molecules on tumor cells are consistent with this supposition (19). In addition, other functions of APLP2 related to cell signaling, adhesion, migration, and proliferation, which may play a role both in normal cell physiology and in malignancy, may all be influenced, directly or indirectly, by the endocytosis of APLP2.…”

Section: Discussionsupporting

confidence: 79%

“…Furthermore, we have shown that APLP2 also 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). The impact of APLP2 on cell surface expression of the MHC class I molecule, and the site of APLP2/MHC class I co-localization within the cell, depends on the specific MHC class I allotype (18).…”

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confidence: 95%

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

Tuli

Sharma

Capek

et al. 2009

Journal of Biological Chemistry

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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 clathrindependent 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.The efficacy of the cellular immune response to intracellular pathogens and tumors is reliant on major histocompatibility complex (MHC) 5 class I molecules. MHC class I molecules present peptides, including peptides derived from pathogens and tumors, at the cell surface to cytotoxic T lymphocytes.Cytotoxic T lymphocytes have been selected during development for their ability to react to cells in the periphery expressing self MHC class I molecules bearing non-self peptides. The level of cell surface expression of MHC class I molecules on infected and malignant cells therefore dictates the extent to which the antigen-specific cytotoxic T lymphocytes can recognize, and subsequently lyse, abnormal cells. The cell surface expression of MHC class I molecules is controlled by the quantity and quality of MHC class I molecules that are assembled, and also by the rate at which MHC class I molecules depart from the plasma membrane.Amyloid precursor-like protein 2 (APLP2) binds to the MHC class I molecule K d in cells that express ␤2-microglobulin (1, 2). 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). APLP2 shares a high degree of sequence homology with APP, particularly at the C-terminal end. However, ...

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Section: Discussionsupporting

confidence: 79%

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confidence: 95%

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

Tuli

Sharma

Capek

et al. 2009

Journal of Biological Chemistry

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Sester

Koebernick

Owen

et al. 2009

The Journal of Immunology

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Successful establishment and persistence of adenovirus (Ad) infections are facilitated by immunosubversive functions encoded in the early transcription unit 3 (E3). The E3/19K protein has a dual role, preventing cell surface transport of MHC class I/HLA class I (MHC-I/HLA-I) Ags and the MHC-I–like molecules (MHC-I chain-related chain A and B [MICA/B]), thereby inhibiting both recognition by CD8 T cells and NK cells. Although some crucial functional elements in E3/19K have been identified, a systematic analysis of the functional importance of individual amino acids is missing. We now have substituted alanine for each of 21 aas in the luminal domain of Ad2 E3/19K conserved among Ads and investigated the effects on HLA-I downregulation by coimmunoprecipitation, pulse-chase analysis, and/or flow cytometry. Potential structural alterations were monitored using conformation-dependent E3/19K-specific mAbs. The results revealed that only a small number of mutations abrogated HLA-I complex formation (e.g., substitutions W52, M87, and W96). Mutants M87 and W96 were particularly interesting as they exhibited only minimal structural changes suggesting that these amino acids make direct contacts with HLA-I. The considerable number of substitutions with little functional defects implied that E3/19K may have additional cellular target molecules. Indeed, when assessing MICA/B cell-surface expression we found that mutation of T14 and M82 selectively compromised MICA/B downregulation with essentially no effect on HLA-I modulation. In general, downregulation of HLA-I was more severely affected than that of MICA/B; for example, substitutions W52, M87, and W96 essentially abrogated HLA-I modulation while largely retaining the ability to sequester MICA/B. Thus, distinct conserved amino acids seem preferentially important for a particular functional activity of E3/19K.

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“…28 Our laboratory recently demonstrated that APLP2 is a pro-survival factor in pancreatic cancer cells and also showed that APLP2 reduces the surface expression of the major histocompatibility complex (MHC) class I molecule (which is vital for T cell recognition and lysis of tumor cells) by an endocytic mechanism. [29][30][31][32][33] Findings from our laboratory and others show that APLP2 is elevated in a variety of cancer cell lines (e.g., pancreatic and prostate cancer cell lines) and in human pancreatic and colorectal cancer tissues. 29,[32][33][34][35][36] Therefore, we hypothesized that APLP2 might be a pro-survival factor in Ewing sarcoma cells.…”

Section: Aplp2 Suppresses the Induction Of Irradiation-induced Apoptomentioning

confidence: 79%

“…[29][30][31][32][33] In contrast to their activation of T cells, MHC class I molecule interaction with inhibitory receptors on NK cells downregulates NK cell cytotoxic function. 46,47 Because LAK cell populations include both T cells and NK cells (e.g., see Fig.…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor-like protein 2 suppresses irradiation-induced apoptosis in Ewing sarcoma cells and is elevated in immune-evasive Ewing sarcoma cells

Peters

Yan

Nordgren

et al. 2013

Cancer Biology & Therapy

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Amyloid precursor-like protein 2 association with HLA class I molecules

Cited by 18 publications

References 51 publications

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

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

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

Amyloid precursor-like protein 2 suppresses irradiation-induced apoptosis in Ewing sarcoma cells and is elevated in immune-evasive Ewing sarcoma cells

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