Proteasomes and antigen presentation: evidence that a KEKE motif does not promote presentation of the class I epitope SIINFEKL

Gonciarz-Swiatek, Malgorzata; Rechsteiner, Martin

doi:10.1016/j.molimm.2005.11.012

Cited by 8 publications

(6 citation statements)

References 37 publications

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“…More recent studies, however, demonstrated that hsp90 binds proteasome‐generated protein fragments to protect these from further degradation, and makes such fragments available for MHC class I loading 46, 47. Thus, hsp90 acts downstream of the proteasome, which was confirmed also for PA28‐deficient cells 28. Also our finding that MHC class I expression levels are reduced on PA28‐deficient compared with wt spleen cells implies that any compensatory effects of hsp90 on the peptide pool available for MHC class I binding in the absence of PA28 are partial at most, and is consistent with the notion that the hsp90 pathway does not produce new MHC class I ligands but enhances the presentation of peptides that are produced by the proteasome.…”

Section: Discussionmentioning

confidence: 79%

“…Notably, peritoneal macrophages of these mice failed to upregulate MHC class I cell‐surface expression following IFN‐γ treatment 27. Such defects in MHC class I upregulation were not observed in mouse embryonic cells of these gene‐deficient mice 28. Taken together, these studies suggest that the effects of PA28 on antigen processing and immune responses are rather mild.…”

Section: Introductionmentioning

confidence: 80%

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PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I‐binding peptides in vivo

Graaf¹,

Helden²,

Textoris-Taube³

et al. 2011

Eur J Immunol

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Summary Proteasomes play a fundamental role in the processing of intracellular antigens into peptides that bind to MHC class I molecules for presentation to CD8 T cells. Three IFNγ-inducible catalytic proteasome (immuno)subunits as well as the IFNγ-inducible proteasome activator PA28 dramatically accelerate the generation of a subset of MHC class I-presented antigenic peptides. To determine whether these IFNγ-inducible proteasome components play a compounded role in antigen processing, we generated mice lacking both PA28 and the immunosubunits β5i/LMP7 and β2i/MECL-1. Analyses of MHC class I cell surface levels ex vivo demonstrated that PA28-deficiency reduced the production of MHC class I-binding peptides both in cells with and without immunosubunits, in the last cells on top of an already diminished production of MHC ligands in the absence of immunoproteasomes. In contrast, the immunosubunits but not PA28 appeared to be of critical importance for the induction of CD8 T cell responses to multiple dominant Influenza and Listeria-derived epitopes. Taken together, our data demonstrate that PA28 and the proteasome immunosubunits use fundamentally different mechanisms to enhance the supply of MHC class I-binding peptides. However, only the immunosubunit-imposed effects on proteolytic epitope processing appear to have substantial effects on the fine-specificity of pathogen-specific CD8 T cell responses.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 80%

PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I‐binding peptides in vivo

Graaf¹,

Helden²,

Textoris-Taube³

et al. 2011

Eur J Immunol

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“…Following in the example of the original paper, osmotic lysis of pinosomes has been particularly used for intracellular delivery of proteins 174,175,970–984 , antibodies 976,985–989 , dextrans 174,989–991 , and peptides 992–994 . In a landmark paper in 1988, osmotic lysis of pinosomes was used to prove that cytosolic loading of proteins could mediate their presentation as antigens through the major histone compatibility I pathway to invoke a specific immune response 175 .…”

Section: Intracellular Delivery By Permeabilizationmentioning

confidence: 99%

Intracellular Delivery by Membrane Disruption: Mechanisms, Strategies, and Concepts

2018

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Intracellular delivery is a key step in biological research and has enabled decades of biomedical discoveries. It is also becoming increasingly important in industrial and medical applications ranging from biomanufacture to cell-based therapies. Here, we review techniques for membrane disruption-based intracellular delivery from 1911 until the present. These methods achieve rapid, direct, and universal delivery of almost any cargo molecule or material that can be dispersed in solution. We start by covering the motivations for intracellular delivery and the challenges associated with the different cargo types-small molecules, proteins/peptides, nucleic acids, synthetic nanomaterials, and large cargo. The review then presents a broad comparison of delivery strategies followed by an analysis of membrane disruption mechanisms and the biology of the cell response. We cover mechanical, electrical, thermal, optical, and chemical strategies of membrane disruption with a particular emphasis on their applications and challenges to implementation. Throughout, we highlight specific mechanisms of membrane disruption and suggest areas in need of further experimentation. We hope the concepts discussed in our review inspire scientists and engineers with further ideas to improve intracellular delivery.

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“…However, it was also proposed that KEKE motifs do not enhance presentation of the OVA epitope. On the other hand, studies did confirm that PA28-ab is needed for efficient SIINFEKL surface expression when hsp90 is inhibited [27]. The indels noted in the carp KEKE motifs indicate a flexibility in the length of this motif.…”

Section: Discussionmentioning

confidence: 99%

Molecular cloning and tissue transcriptional analysis of a novel gene encoding proteasome activator PA28-α from common carp (Cyprinus carpio L.)

Tan

Lü

et al. 2010

Fish Sci

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To identify the homolog of the PA28-a subunit, a leukocyte cDNA library of common carp was screened and the full-length cDNA sequence of the PSME1 gene coding for the PA28-a was obtained. It encompasses 1097 nucleotides (nt), with an open reading frame encoding 249 amino acids. The deduced protein sequence exhibits identities of 92, 78, 78, 77, 75, 56, 54, 53 and 54% with zebrafish, Atlantic salmon, northern pike, rainbow trout, rainbow smelt, mouse, pig, cattle and human PA28-a subunits, respectively. Multiple sequence alignment of the PA28-a protein of common carp and other known PA28 subunits indicates that it contains a PA28-a subunit-specific insert corresponding to the KEKE motif of the known PA28-a (Region B), a characteristic proline-rich motif (Region A), a potential protein kinase C recognition site (Region D), a conserved activation loop (Region C), and a highly homologous C-terminal region (Region E). Phylogenetic analysis reveals that the PA28-c subunit is related to the presumed ancestor of the PA28-a and PA28-b subunits. In addition, the genomic DNA obtained by PCR is composed of eleven exons and ten introns with 3583 nt, typical of the PA28-a gene organization. Compared with the other known PA28-a genomic DNA, in spite of structural conservation through evolution, the fish PA28-a genes showed a much greater sequence divergence than their counterparts among mammals. Tissue transcriptional analysis of carp PA28-a indicated that it was visibly enhanced in tissues associated with immunity (gill, spleen, kidney and liver), and weakly transcribed in muscle, brain and heart.

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Proteasomes and antigen presentation: evidence that a KEKE motif does not promote presentation of the class I epitope SIINFEKL

Cited by 8 publications

References 37 publications

PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I‐binding peptides in vivo

PA28 and the proteasome immunosubunits play a central and independent role in the production of MHC class I‐binding peptides in vivo

Intracellular Delivery by Membrane Disruption: Mechanisms, Strategies, and Concepts

Molecular cloning and tissue transcriptional analysis of a novel gene encoding proteasome activator PA28-α from common carp (Cyprinus carpio L.)

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