Autophagy mediates transporter associated with antigen processing-independent presentation of viral epitopes through MHC class I pathway

Blood ◽  
2012 ◽  
Vol 120 (5) ◽  
pp. 994-1004 ◽  
Author(s):  
Siok-Keen Tey ◽  
Rajiv Khanna
Keyword(s):  
Endoplasmic Reticulum ◽  
Mhc Class I ◽  
Immune Evasion ◽  
Antigen Processing ◽  
Secretory Pathway ◽  
Proteasomal Degradation ◽  
Class I ◽  
Acid Stability ◽  
Peptide Epitopes ◽  
Viral Immune Evasion

Abstract The endogenous presentation of the majority of viral epitopes through MHC class I pathway is strictly dependent on the transporter associated with antigen processing (TAP) complex, which transfers the peptide products of proteasomal degradation into the endoplasmic reticulum. A small number of epitopes can be presented through the TAP-independent pathway, the precise mechanism for which remains largely unresolved. Here we show that TAP-independent presentation can be mediated by autophagy and that this process uses the vacuolar pathway and not the conventional secretory pathway. After macroautophagy, the antigen is processed through a proteasome-independent pathway, and the peptide epitopes are loaded within the autophagolysosomal compartment in a process facilitated by the relative acid stability of the peptide-MHC interaction. Despite bypassing much of the conventional MHC class I pathway, the autophagy-mediated pathway generates the same epitope as that generated through the conventional pathway and thus may have a role in circumventing viral immune evasion strategies that primarily target the conventional pathway.

New insights into the structure of the MHC class I peptide-loading complex and mechanisms of TAP inhibition by viral immune evasion proteins

2019 ◽  
Vol 113 ◽  
pp. 103-114 ◽  
Author(s):  
Patrique Praest ◽  
A. Manuel Liaci ◽  
Friedrich Förster ◽  
Emmanuel J.H.J. Wiertz
Keyword(s):  
Mhc Class I ◽  
Immune Evasion ◽  
Class I ◽  
Viral Immune Evasion ◽  
Peptide Loading

Viral immune evasion: Lessons in MHC class I antigen presentation

2015 ◽  
Vol 27 (2) ◽  
pp. 125-137 ◽  
Author(s):  
Michael L. van de Weijer ◽  
Rutger D. Luteijn ◽  
Emmanuel J.H.J. Wiertz
Keyword(s):  
Antigen Presentation ◽  
Mhc Class I ◽  
Immune Evasion ◽  
Class I ◽  
Viral Immune Evasion ◽  
Mhc Class I Antigen

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

2001 ◽  
Vol 75 (12) ◽  
pp. 5663-5671 ◽  
Author(s):  
Frank Momburg ◽  
Arno Müllbacher ◽  
Mario Lobigs
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Surface Expression ◽  
Class I ◽  
Peptide Transport ◽  
Cell Surface Expression ◽  
Flavivirus Infection ◽  
Mhc Class I Molecules

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.

scholarly journals Identification of human cancers deficient in antigen processing.

1993 ◽  
Vol 177 (2) ◽  
pp. 265-272 ◽  
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.

scholarly journals Endoplasmic Reticulum Aminopeptidase Associated with Antigen Processing Defines the Composition and Structure of MHC Class I Peptide Repertoire in Normal and Virus-Infected Cells

2010 ◽  
Vol 184 (6) ◽  
pp. 3033-3042 ◽  
Author(s):  
Nicolas Blanchard ◽  
Takayuki Kanaseki ◽  
Hernando Escobar ◽  
Frédéric Delebecque ◽  
Niranjana A. Nagarajan ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Mhc Class I ◽  
Antigen Processing ◽  
Class I ◽  
Composition And Structure ◽  
Infected Cells

scholarly journals Association of immunoproteasomes with the endoplasmic reticulum

2000 ◽  
Vol 352 (3) ◽  
pp. 611-615 ◽  
Author(s):  
Paul BROOKS ◽  
Rachael Z. MURRAY ◽  
Grant G. F. MASON ◽  
Klavs B. HENDIL ◽  
A. Jennifer RIVETT
Keyword(s):  
Endoplasmic Reticulum ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Critical Role ◽  
Class I ◽  
Specialized Function ◽  
Delta Subunit ◽  
Intracellular Proteolysis ◽  
Γ Interferon

Proteasomes are complex multisubunit proteases which play a critical role in intracellular proteolysis. Immunoproteasomes, which contain three γ-interferon-inducible subunits, are a subset of proteasomes which have a specialized function in antigen processing for presentation by the MHC class I pathway. Two of the γ-interferon inducible subunits, LMP2 and LMP7, are encoded within the MHC class II region adjacent to the two TAP (transporter associated with antigen presentation) genes. We have investigated the localization of immunoproteasomes using monoclonal antibodies to LMP2 and LMP7. Immunoproteasomes were strongly enriched around the endoplasmic reticulum as judged by double-immunofluorescence experiments with anti-calreticulin antibodies, but were also present in the nucleus and throughout the cytosol. In contrast, proteasome subunit C2, which is present in all proteasomes, was found to be evenly distributed throughout the cytoplasm and in the nucleus, as was the delta subunit, which is replaced by LMP2 in immunoproteasomes. γ-Interferon increased the level of immunoproteasomes, but had no effect on their distribution. Our results provide the first direct evidence that immunoproteasomes are strongly enriched at the endoplasmic reticulum, where they may be located close to the TAP transporter to provide efficient transport of peptides into the lumen of the endoplasmic recticulum for association with MHC class I molecules.

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