Modulation of Transporter Associated with Antigen Processing (TAP)-Mediated Peptide Import into the Endoplasmic Reticulum by Flavivirus Infection

ABSTRACT In contrast to many other viruses that escape the cellular immune response by downregulating major histocompatibility complex (MHC) class I molecules, flavivirus infection can upregulate their cell surface expression. Previously we have presented evidence that during flavivirus infection, peptide supply to the endoplasmic reticulum is increased (A. Müllbacher and M. Lobigs, Immunity 3:207–214, 1995). Here we show that during the early phase of infection with different flaviviruses, the transport activity of the peptide transporter associated with antigen processing (TAP) is augmented by up to 50%. TAP expression is unaltered during infection, and viral but not host macromolecular synthesis is required for enhanced peptide transport. This study is the first demonstration of transient enhancement of TAP-dependent peptide import into the lumen of the endoplasmic reticulum as a consequence of a viral infection. We suggest that the increased supply of peptides for assembly with MHC class I molecules in flavivirus-infected cells accounts for the upregulation of MHC class I cell surface expression with the biological consequence of viral evasion of natural killer cell recognition.

Download Full-text

Crystal structures of lysophospholipid-bound MHC class I molecules

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011932 ◽

2020 ◽

Vol 295 (20) ◽

pp. 6983-6991 ◽

Cited By ~ 1

Author(s):

Yoko Shima ◽

Daisuke Morita ◽

Tatsuaki Mizutani ◽

Naoki Mori ◽

Bunzo Mikami ◽

...

Keyword(s):

Cell Surface ◽

Crystal Structures ◽

Mhc Class I ◽

Antigen Processing ◽

Surface Expression ◽

Class I ◽

Cell Surface Expression ◽

Peptide Antigens ◽

Histocompatibility Complex ◽

Mhc Class I Molecules

Newly synthesized major histocompatibility complex (MHC) class I proteins are stabilized in the endoplasmic reticulum (ER) by binding 8–10-mer-long self-peptide antigens that are provided by transporter associated with antigen processing (TAP). These MHC class I:peptide complexes then exit the ER and reach the plasma membrane, serving to sustain the steady-state MHC class I expression on the cell surface. A novel subset of MHC class I molecules that preferentially bind lipid-containing ligands rather than conventional peptides was recently identified. The primate classical MHC class I allomorphs, Mamu-B*098 and Mamu-B*05104, are capable of binding the N-myristoylated 5-mer (C14-Gly-Gly-Ala-Ile-Ser) or 4-mer (C14-Gly-Gly-Ala-Ile) lipopeptides derived from the N-myristoylated SIV Nef protein, respectively, and of activating lipopeptide antigen-specific cytotoxic T lymphocytes. We herein demonstrate that Mamu-B*098 samples lysophosphatidylethanolamine and lysophosphatidylcholine containing up to a C20 fatty acid in the ER. The X-ray crystal structures of Mamu-B*098 and Mamu-B*05104 complexed with lysophospholipids at high resolution revealed that the B and D pockets in the antigen-binding grooves of these MHC class I molecules accommodate these lipids through a monoacylglycerol moiety. Consistent with the capacity to bind cellular lipid ligands, these two MHC class I molecules did not require TAP function for cell-surface expression. Collectively, these results indicate that peptide- and lipopeptide-presenting MHC class I subsets use distinct sources of endogenous ligands.

Download Full-text

Cell Surface Expression of Major Histocompatibility Complex Class I Molecules Is Reduced in Hepatitis C Virus Subgenomic Replicon-Expressing Cells

Journal of Virology ◽

10.1128/jvi.77.21.11644-11650.2003 ◽

2003 ◽

Vol 77 (21) ◽

pp. 11644-11650 ◽

Cited By ~ 39

Author(s):

Keith D. Tardif ◽

Aleem Siddiqui

Keyword(s):

Major Histocompatibility Complex ◽

Hepatitis C ◽

Cell Surface ◽

Mhc Class I ◽

Surface Expression ◽

Protein Glycosylation ◽

Class I ◽

Cell Surface Expression ◽

Histocompatibility Complex ◽

Mhc Class I Molecules

ABSTRACT The hepatitis C virus (HCV) causes chronic hepatitis in most infected individuals by evading host immune defenses. In this investigation, we show that HCV-infected cells may go undetected in the immune system by suppressing major histocompatibility complex (MHC) class I antigen presentation to cytotoxic T lymphocytes. Cells expressing HCV subgenomic replicons have lower MHC class I cell surface expression. This is due to reduced levels of properly folded MHC class I molecules. HCV replicons induce endoplasmic reticulum (ER) stress (K. Tardif, K. Mori, and A. Siddiqui, J. Virol. 76:7453-7459, 2002), which results from a decline in protein glycosylation. Decreasing protein glycosylation can disrupt protein folding, preventing the assembly of MHC class I molecules. This results in the accumulation of unfolded MHC class I. Therefore, the persistence and pathogenesis of HCV may depend upon the ER stress-mediated interference of MHC class I assembly and cell surface expression.

Download Full-text

E3/19K from adenovirus 2 is an immunosubversive protein that binds to a structural motif regulating the intracellular transport of major histocompatibility complex class I proteins.

Journal of Experimental Medicine ◽

10.1084/jem.172.6.1653 ◽

1990 ◽

Vol 172 (6) ◽

pp. 1653-1664 ◽

Cited By ~ 30

Author(s):

W A Jefferies ◽

H G Burgert

Keyword(s):

Major Histocompatibility Complex ◽

Cell Surface ◽

Mhc Class I ◽

Intracellular Transport ◽

Surface Expression ◽

Class I ◽

Cell Surface Expression ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Mhc Class I Molecules

We have previously expressed in transgenic mice a chimeric H-2Kd/Kk protein called C31, which contains the extracellular alpha 1 domain of Kd, whereas the rest of the molecule is of Kk origin. This molecule functions as a restriction element for alloreactive and influenza A-specific cytotoxic T lymphocytes (CTL) but is only weakly expressed at the cell surface of splenocytes. Here, we show that the low cell surface expression is the result of slow intracellular transport and processing of the C31 protein. A set of hybrid molecules between Kd and Kk were used to localize the regions in major histocompatibility complex (MHC) molecules that are important for their intracellular transport and to further localize the structures responsible for binding to the adenovirus 2 E3/19K protein. This protein appears to be an important mediator of adenovirus persistence. It acts by binding to the immaturely glycosylated forms of MHC class I proteins in the endoplasmic reticulum (ER), preventing their passage to the cell surface and thereby reducing the recognition of infected cells by virus-specific T cells. We find the surprising result that intracellular transport and E3/19K binding are controlled primarily by the first half of the second domain of Kd, thus localizing these phenomena to the five polymorphic residues in this region of the Kd protein. This result implies that the E3/19K protein may act by inhibiting peptide binding or by disrupting the oligomerization of MHC class I molecules required for transport out of the ER. Alternatively, the E3/19K protein may inhibit the function of a positively acting transport molecule necessary for cell surface expression of MHC class I molecules.

Download Full-text

The Transporter Associated With Antigen Processing: Function and Implications in Human Diseases

Physiological Reviews ◽

10.1152/physrev.00025.2001 ◽

2002 ◽

Vol 82 (1) ◽

pp. 187-204 ◽

Cited By ~ 120

Author(s):

Brigitte Lankat-Buttgereit ◽

Robert Tampé

Keyword(s):

Cell Surface ◽

Mhc Class I ◽

Antigen Processing ◽

Immune Surveillance ◽

Class I ◽

Cell Surface Expression ◽

Atp Binding ◽

Binding Motif ◽

Antigenic Peptides ◽

Mhc Class I Molecules

The adaptive immune systems have evolved to protect the organism against pathogens encountering the host. Extracellular occurring viruses or bacteria are mainly bound by antibodies from the humoral branch of the immune response, whereas infected or malignant cells are identified and eliminated by the cellular immune system. To enable the recognition, proteins are cleaved into peptides in the cytosol and are presented on the cell surface by class I molecules of the major histocompatibility complex (MHC). The transport of the antigenic peptides into the lumen of the endoplasmic reticulum (ER) and loading onto the MHC class I molecules is an essential process for the presentation to cytotoxic T lymphocytes. The delivery of these peptides is performed by the transporter associated with antigen processing (TAP). TAP is a heterodimer of TAP1 and TAP2, each subunit containing transmembrane domains and an ATP-binding motif. Sequence homology analysis revealed that TAP belongs to the superfamily of ATP-binding cassette transporters. Loss of TAP function leads to a loss of cell surface expression of MHC class I molecules. This may be a strategy for tumors and virus-infected cells to escape immune surveillance. Structure and function of the TAP complex as well as the implications of loss or downregulation of TAP is the topic of this review.

Download Full-text

Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding

eLife ◽

10.7554/elife.05345 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 63

Author(s):

Paul E Chappell ◽

El Kahina Meziane ◽

Michael Harrison ◽

Łukasz Magiera ◽

Clemens Hermann ◽

...

Keyword(s):

Cell Surface ◽

Mhc Class I ◽

Peptide Binding ◽

Fundamental Property ◽

Surface Expression ◽

Pathogen Resistance ◽

Class I ◽

Cell Surface Expression ◽

Mhc Molecules ◽

Mhc Class I Molecules

Highly polymorphic major histocompatibility complex (MHC) molecules are at the heart of adaptive immune responses, playing crucial roles in many kinds of disease and in vaccination. We report that breadth of peptide presentation and level of cell surface expression of class I molecules are inversely correlated in both chickens and humans. This relationship correlates with protective responses against infectious pathogens including Marek's disease virus leading to lethal tumours in chickens and human immunodeficiency virus infection progressing to AIDS in humans. We propose that differences in peptide binding repertoire define two groups of MHC class I molecules strategically evolved as generalists and specialists for different modes of pathogen resistance. We suggest that differences in cell surface expression level ensure the development of optimal peripheral T cell responses. The inverse relationship of peptide repertoire and expression is evidently a fundamental property of MHC molecules, with ramifications extending beyond immunology and medicine to evolutionary biology and conservation.

Download Full-text

Release from Endoplasmic Reticulum Matrix Proteins Controls Cell Surface Transport of MHC Class I Molecules

Traffic ◽

10.1111/tra.12279 ◽

2015 ◽

Vol 16 (6) ◽

pp. 591-603 ◽

Cited By ~ 4

Author(s):

Susanne Fritzsche ◽

Esam T. Abualrous ◽

Britta Borchert ◽

Frank Momburg ◽

Sebastian Springer

Keyword(s):

Endoplasmic Reticulum ◽

Cell Surface ◽

Mhc Class I ◽

Matrix Proteins ◽

Class I ◽

Surface Transport ◽

Mhc Class I Molecules

Download Full-text

Identification of human cancers deficient in antigen processing.

Journal of Experimental Medicine ◽

10.1084/jem.177.2.265 ◽

1993 ◽

Vol 177 (2) ◽

pp. 265-272 ◽

Cited By ~ 391

Author(s):

N P Restifo ◽

F Esquivel ◽

Y Kawakami ◽

J W Yewdell ◽

J J Mulé ◽

...

Keyword(s):

T Cells ◽

Endoplasmic Reticulum ◽

Mhc Class I ◽

Cell Lines ◽

Antigen Processing ◽

Human Tumor ◽

Class I ◽

Cell Lung Carcinoma ◽

Mhc Molecules ◽

Mhc Class I Molecules

Intracellular antigens must be processed before presentation to CD8+ T cells by major histocompatibility complex (MHC) class I molecules. Using a recombinant vaccinia virus (Vac) to transiently express the Kd molecule, we studied the antigen processing efficiency of 26 different human tumor lines. Three cell lines, all human small cell lung carcinoma, consistently failed to process endogenously synthesized proteins for presentation to Kd-restricted, Vac-specific T cells. Pulse-chase experiments showed that MHC class I molecules were not transported by these cell lines from the endoplasmic reticulum to the cell surface. This finding suggested that peptides were not available for binding to nascent MHC molecules in the endoplasmic reticulum. Northern blot analysis of these cells revealed low to nondetectable levels of mRNAs for MHC-encoded proteasome components LMP-7 and LMP-2, as well as the putative peptide transporters TAP-1 and TAP-2. Treatment of cells with interferon gamma enhanced expression of these mRNAs and reversed the observed functional and biochemical deficits. Our findings suggest that downregulation of antigen processing may be one of the strategies used by tumors to escape immune surveillance. Potential therapeutic applications of these findings include enhancing antigen processing at the level of the transcription of MHC-encoded proteasome and transporter genes.

Download Full-text