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5. Supplementary Methods and Figure Legends from Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Author

Młynarczuk-Biały, Izabela, primary, Roeckmann, Heike, primary, Kuckelkorn, Ulrike, primary, Schmidt, Boris, primary, Umbreen, Sumaira, primary, Gołąb, Jakub, primary, Ludwig, Antje, primary, Montag, Christina, primary, Wiebusch, Lüder, primary, Hagemeier, Christian, primary, Schadendorf, Dirk, primary, Kloetzel, Peter-M., primary, and Seifert, Ulrike, primary

Published
2023
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6. Supplementary Figure 1 from Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Author

Młynarczuk-Biały, Izabela, primary, Roeckmann, Heike, primary, Kuckelkorn, Ulrike, primary, Schmidt, Boris, primary, Umbreen, Sumaira, primary, Gołąb, Jakub, primary, Ludwig, Antje, primary, Montag, Christina, primary, Wiebusch, Lüder, primary, Hagemeier, Christian, primary, Schadendorf, Dirk, primary, Kloetzel, Peter-M., primary, and Seifert, Ulrike, primary

Published
2023
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7. Supplementary Figure 2 from Combined Effect of Proteasome and Calpain Inhibition on Cisplatin-Resistant Human Melanoma Cells

Author

Młynarczuk-Biały, Izabela, primary, Roeckmann, Heike, primary, Kuckelkorn, Ulrike, primary, Schmidt, Boris, primary, Umbreen, Sumaira, primary, Gołąb, Jakub, primary, Ludwig, Antje, primary, Montag, Christina, primary, Wiebusch, Lüder, primary, Hagemeier, Christian, primary, Schadendorf, Dirk, primary, Kloetzel, Peter-M., primary, and Seifert, Ulrike, primary

Published
2023
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18. IFN-[gamma]-induced immune adaptation of the proteasome system is an accelerated and transient response

Author

Heink, Sylvia, Ludwig, Daniela, Kloetzel, Peter-M., and Kruger, Elke

Subjects
Ubiquitin-proteasome system -- Research, Peptides -- Research, Science and technology
Abstract

Peptide generation by the proteasome is rate-limiting in MHC class I-restricted antigen presentation in response to IFN-[gamma] IFN-[gamma]-induced de novo formation of immunoproteasomes, therefore, essentially supports the rapid adjustment of the mammalian immune system. Here, we report that the molecular interplay between the proteasome maturation protein (POMP) and the proteasomal [beta]5i subunit low molecular weight protein 7 (LMP7) has a key position in this immune adaptive program. IFN-[gamma]-induced coincident biosynthesis of POMP and LMP7 and their direct interaction essentially accelerate immunoproteasome biogenesis compared with constitutive 20S proteasome assembly. The dynamics of this process is determined by rapid LMP7 activation and the immediate LMP7-dependent degradation of POMP. Silencing of POMP expression impairs recruitment of both [beta]5 subunits into the proteasome complex, resulting in decreased proteasome activity, reduced MHC class I surface expression, and induction of apoptosis. Furthermore, our data reveal that immunoproteasomes exhibit a considerably shortened half-life, compared with constitutive proteasomes. In consequence, our studies demonstrate that the cytokine-induced rapid immune adaptation of the proteasome system is a tightly regulated and transient response allowing cells to return rapidly to a normal situation once immunoproteasome function is no longer required. antigen presentation | immunoproteasome | MHC class |

Published
2005

22. PI31 is a modulator of proteasome formation and antigen processing

Author

Zaiss, Dietmar M.W., Standera, Sybille, Kloetzel, Peter-M., and Sijts, Alice J.A.M.

Subjects
Antigens -- Physiological aspects, Peptides -- Physiological aspects, Proteins -- Physiological aspects, Science and technology
Abstract

Regulation of the proteasome system, which is responsible for the generation of most MHC class I-bound peptides, occurs through the interaction of the 20S proteasome with several regulatory proteins. One of these is PI31, which acts in vitro as an inhibitor of proteasome activity. Here, we demonstrate that, rather than inhibiting proteasome function, PI31 acts as a selective modulator of the proteasome-mediated steps in MHC class I antigen processing. Overexpression of PI31 in mouse embryonic cells has no impact on proteasome-mediated proteolysis. Instead, PI31, which localizes at the nuclear envelope/endoplasmic reticulum membrane, selectively interferes with the maturation of immunoproteasome precursor complexes. Consequently, overexpression of PI31 abrogates MHC class I presentation of an immunoproteasome-dependent cytotoxic T lymphocyte epitope and reduces the surface MHC class I levels on IFN-[gamma]-treated mouse embryonic cells. Thus, PI31 represents a cellular regulator of proteasome formation and of proteasome-mediated antigen processing.

Published
2002

29. Coordinated dual cleavages induced by the proteasome regulator PA28 lead to dominant MHC ligands

Author

Dick, Tobias P., Ruppert, Thomas, Groettrup, Marcus, Kloetzel, Peter M., Kuehn, Lothar, Koszinowski, Ulrich H., Stevanovic, Stefan, Schild, Hansjorg, and Rammensee, Hans-Georg

Subjects
Proteases -- Research, Major histocompatibility complex -- Research, Ligands (Biochemistry) -- Research, Scission (Chemistry) -- Research, Biological sciences
Abstract

The gamma-interferon inducible PA28 protein complex, or 11S regulator, which is composed of two homologous subunit forming a hexa- or heptameric ring structure, is known to associate with the 20S proteasome particle. The kinetics of product generation by 20S proteasomes with and without PA28 is studied. Results indicate that the PA28 regulator significantly alters the cleavage mechanism of the proteasome and optimizes the generation of dominant T cell epitopes.

Published
1996

32. CD8+T cells ofListeria monocytogenes-infected mice recognize both linear and spliced proteasome products

Author

Platteel, Anouk C M, Mishto, Michele, Textoris-Taube, Kathrin, Keller, Christin, Liepe, Juliane, Busch, Dirk H, Kloetzel, Peter M, Sijts, Alice J A M, LS Immunologie, and dI&I RA-I&I I&I

Subjects
0301 basic medicine, Proteasome Endopeptidase Complex, Immunology, Antigen presentation, Epitopes, T-Lymphocyte, CD8-Positive T-Lymphocytes, CD8+ T cells, Major histocompatibility complex, Mass Spectrometry, Epitope, Mice, 03 medical and health sciences, 0302 clinical medicine, Antigen, MHC class I, Animals, Protein Splicing, Immunology and Allergy, Cytotoxic T cell, Computer Simulation, Listeriosis, Immune Evasion, Antigen Presentation, Proteasome, biology, Linear epitope, Histocompatibility Antigens Class I, MHC class I antigen processing, Listeria monocytogenes, Molecular biology, Tumor antigen, 030104 developmental biology, biology.protein, Peptides, Proteasome-catalyzed peptide splicing, 030215 immunology
Abstract

CD8(+) T cells responding to infection recognize pathogen-derived epitopes presented by MHC class-I molecules. While most of such epitopes are generated by proteasome-mediated antigen cleavage, analysis of tumor antigen processing has revealed that epitopes may also derive from proteasome-catalyzed peptide splicing (PCPS). To determine whether PCPS contributes to epitope processing during infection, we analyzed the fragments produced by purified proteasomes from a Listeria monocytogenes polypeptide. Mass spectrometry identified a known H-2K(b) -presented linear epitope (LLO296-304 ) in the digests, as well as four spliced peptides that were trimmed by ERAP into peptides with in silico predicted H-2K(b) binding affinity. These spliced peptides, which displayed sequence similarity with LLO296-304 , bound to H-2K(b) molecules in cellular assays and one of the peptides was recognized by CD8(+) T cells of infected mice. This spliced epitope differed by one amino acid from LLO296-304 and double staining with LLO296-304 - and spliced peptide-folded MHC multimers showed that LLO296-304 and its spliced variant were recognized by the same CD8(+) T cells. Thus, PCPS multiplies the variety of peptides that is processed from an antigen and leads to the production of epitope variants that can be recognized by cross-reacting pathogen-specific CD8(+) T cells. Such mechanism may reduce the chances for pathogen immune evasion. This article is protected by copyright. All rights reserved.

Published
2016
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42. Role of peptide processing predictions in T cell epitope identification: contribution of different prediction programs

Author

Calis, Jorg J A, Reinink, Peter, Keller, Christin, Kloetzel, Peter M, Kesmir, Can, Sub Theoretical Biology, Sub Theoretical Biology & Bioinformatics, LS Immunologie, Theoretical Biology and Bioinformatics, Sub Theoretical Biology, Sub Theoretical Biology & Bioinformatics, LS Immunologie, and Theoretical Biology and Bioinformatics

Subjects
Proteases, Proteasome Endopeptidase Complex, Proteasomal cleavage, HIV Antigens, Proteolysis, Immunology, Antigen presentation, Epitopes, T-Lymphocyte, Peptide, Protein degradation, Biology, Ligands, 03 medical and health sciences, 0302 clinical medicine, In vivo, Genetics, medicine, Humans, Databases, Protein, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Original Paper, Antigen Presentation, Binding Sites, medicine.diagnostic_test, Histocompatibility Antigens Class I, In vitro, Peptide Fragments, Biochemistry, Proteasome, chemistry, MHC-I presentation, 030220 oncology & carcinogenesis, HIV-1, Peptide processing, Software
Abstract

Proteolysis is the general term to describe the process of protein degradation into peptides. Proteasomes are the main actors in cellular proteolysis, and their activity can be measured in in vitro digestion experiments. However, in vivo proteolysis can be different than what is measured in these experiments if other proteases participate or if proteasomal activity is different in vivo. The in vivo proteolysis can be measured only indirectly, by the analysis of peptides presented on MHC-I molecules. MHC-I presented peptides are protected from further degradation, thus enabling an indirect view on the underlying in vivo proteolysis. The ligands presented on different MHC-I molecules enable different views on this process; in combination, they might give a complete picture. Based on in vitro proteasome-only digestions and MHC-I ligand data, different proteolysis predictors have been developed. With new in vitro digestion and MHC-I ligand data sets, we benchmarked how well these predictors capture in vitro proteasome-only activity and in vivo whole-cell proteolysis, respectively. Even though the in vitro proteasome digestion patterns were best captured by methods trained on such data (ProteaSMM and NetChop 20S), the in vivo whole-cell proteolysis was best predicted by a method trained on MHC-I ligand data (NetChop Cterm). Follow-up analysis showed that the likely source of this difference is the activity from proteases other than the proteasome, such as TPPII. This non-proteasomal in vivo activity is captured by NetChop Cterm and should be taken into account in MHC-I ligand predictions. Electronic supplementary material The online version of this article (doi:10.1007/s00251-014-0815-0) contains supplementary material, which is available to authorized users.

Published
2014

45. Multi-level Strategy for Identifying Proteasome-Catalyzed Spliced Epitopes Targeted by CD8(+) T Cells during Bacterial Infection

Author

Platteel, Anouk C M, Liepe, Juliane, Textoris-Taube, Kathrin, Keller, Christin, Henklein, Petra, Schalkwijk, Hanna H, Cardoso, Rebeca, Kloetzel, Peter M, Mishto, Michele, Sijts, Alice J A M, Platteel, Anouk C M, Liepe, Juliane, Textoris-Taube, Kathrin, Keller, Christin, Henklein, Petra, Schalkwijk, Hanna H, Cardoso, Rebeca, Kloetzel, Peter M, Mishto, Michele, and Sijts, Alice J A M

Abstract

Proteasome-catalyzed peptide splicing (PCPS) generates peptides that are presented by MHC class I molecules, but because their identification is challenging, the immunological relevance of spliced peptides remains unclear. Here, we developed a reverse immunology-based multi-level approach to identify proteasome-generated spliced epitopes. Applying this strategy to a murine Listeria monocytogenes infection model, we identified two spliced epitopes within the secreted bacterial phospholipase PlcB that primed antigen-specific CD8(+) T cells in L. monocytogenes-infected mice. While reacting to the spliced epitopes, these CD8(+) T cells failed to recognize the non-spliced peptide parts in the context of their natural flanking sequences. Thus, we here show that PCPS expands the CD8(+) T cell response against L. monocytogenes by exposing spliced epitopes on the cell surface. Moreover, our multi-level strategy opens up opportunities to systematically investigate proteins for spliced epitope candidates and thus strategies for immunotherapies or vaccine design.

Published
2017

46. Multi-level Strategy for Identifying Proteasome-Catalyzed Spliced Epitopes Targeted by CD8(+) T Cells during Bacterial Infection

Author

dI&I RA-I&I I&I, Platteel, Anouk C M, Liepe, Juliane, Textoris-Taube, Kathrin, Keller, Christin, Henklein, Petra, Schalkwijk, Hanna H, Cardoso, Rebeca, Kloetzel, Peter M, Mishto, Michele, Sijts, Alice J A M, dI&I RA-I&I I&I, Platteel, Anouk C M, Liepe, Juliane, Textoris-Taube, Kathrin, Keller, Christin, Henklein, Petra, Schalkwijk, Hanna H, Cardoso, Rebeca, Kloetzel, Peter M, Mishto, Michele, and Sijts, Alice J A M

Published
2017

47. CD8(+) T cells of Listeria monocytogenes-infected mice recognize both linear and spliced proteasome products

Author

Platteel, Anouk C M, Mishto, Michele, Textoris-Taube, Kathrin, Keller, Christin, Liepe, Juliane, Busch, Dirk H, Kloetzel, Peter M, Sijts, Alice J A M, LS Immunologie, and dI&I RA-I&I I&I

Subjects
Proteasome, MHC class I antigen processing, CD8+ T cells, Listeria monocytogenes, Proteasome-catalyzed peptide splicing
Abstract

CD8(+) T cells responding to infection recognize pathogen-derived epitopes presented by MHC class-I molecules. While most of such epitopes are generated by proteasome-mediated antigen cleavage, analysis of tumor antigen processing has revealed that epitopes may also derive from proteasome-catalyzed peptide splicing (PCPS). To determine whether PCPS contributes to epitope processing during infection, we analyzed the fragments produced by purified proteasomes from a Listeria monocytogenes polypeptide. Mass spectrometry identified a known H-2K(b) -presented linear epitope (LLO296-304 ) in the digests, as well as four spliced peptides that were trimmed by ERAP into peptides with in silico predicted H-2K(b) binding affinity. These spliced peptides, which displayed sequence similarity with LLO296-304 , bound to H-2K(b) molecules in cellular assays and one of the peptides was recognized by CD8(+) T cells of infected mice. This spliced epitope differed by one amino acid from LLO296-304 and double staining with LLO296-304 - and spliced peptide-folded MHC multimers showed that LLO296-304 and its spliced variant were recognized by the same CD8(+) T cells. Thus, PCPS multiplies the variety of peptides that is processed from an antigen and leads to the production of epitope variants that can be recognized by cross-reacting pathogen-specific CD8(+) T cells. Such mechanism may reduce the chances for pathogen immune evasion. This article is protected by copyright. All rights reserved.

Published
2016

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