Post-proteasomal and proteasome-independent generation of MHC class I ligands

Endert, Peter Van

doi:10.1007/s00018-011-0662-1

Cited by 66 publications

(52 citation statements)

References 125 publications

(205 reference statements)

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“…It hinders simple distinction between an increase in proteins misfolding and DRiPs production and increase in the activity of nonproteasomal proteolytic pathways, caused by the cellular stress induced by the proteasome inhibition. The existence of alternative production pipelines for MHC peptides, supplementing the peptide pool when the proteasomes are inhibited, was already suggested by (30), (reviewed in (7,14)). It was also suggested that an alternative proteolytic pathway may be responsible for production of MHC peptides from DRiPs (60).…”

Section: Discussionmentioning

confidence: 95%

The Effect of Proteasome Inhibition on the Generation of the Human Leukocyte Antigen (HLA) Peptidome

Milner

Gutter-Kapon

Bassani-Strenberg

et al. 2013

Molecular & Cellular Proteomics

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The Major histocompatibility complex (MHC) class I peptidome is thought to be generated mostly through proteasomal degradation of cellular proteins, a notion that is based on the alterations in presentation of selected peptides following proteasome inhibition. We evaluated the effects of proteasome inhibitors, epoxomicin and bortezomib, on human cultured cancer cells. Because the inhibitors did not reduce the level of presentation of the cell surface human leukocyte antigen (HLA) molecules, we followed their effects on the rates of synthesis of both HLA peptidome and proteome of the cells, using dynamic stable isotope labeling in tissue culture (dynamic-SILAC). The inhibitors reduced the rates of synthesis of most cellular proteins and HLA peptides, yet the synthesis rates of some of the proteins and HLA peptides was not decreased by the inhibitors and of some even increased. Therefore, we concluded that the inhibitors affected the production of the HLA peptidome in a complex manner, including modulation of the synthesis rates of the source proteins of the HLA peptides, in addition to their effect on their degradation. The collected data may suggest that the current reliance on proteasome inhibition may overestimate the centrality of the proteasome in the generation of the MHC peptidome. It is therefore suggested that the relative contribution of the proteasomal and nonproteasomal pathways to the production of the MHC peptidome should be revaluated in accordance with the inhibitors effects on the synthesis rates of the source proteins of the MHC peptides. Molecular & Cellular Proteomics 12:

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Section: Discussionmentioning

confidence: 95%

The Effect of Proteasome Inhibition on the Generation of the Human Leukocyte Antigen (HLA) Peptidome

Milner

Gutter-Kapon

Bassani-Strenberg

et al. 2013

Molecular & Cellular Proteomics

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“…the first identified endogenous substrate of DPP9 was the tumor-related epitope RU1 [34][35][36][37][38][39][40][41][42] . Its hydrolysis by DPP9 results in its limited presentation on MhC class I molecules to the immune system linking DPP9 to the MhC class I antigen presentation pathway [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

Justa-Schuch

Möller

Geiss‐Friedlander

2014

Cell. Mol. Life Sci.

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“…Cells were stained with anti-insulin Ab diluted at 1:50 in PBS with 0.1% saponin and 2% FBS for 30 min at RT followed by Alexa 594-coupled goat anti-rabbit Abs diluted 1:200 for 30 min at RT. Stained cells were again fixed for 10 min at RT, and the reaction stopped with 50 mM NH 4 Cl in PBS for 5 min. Finally, coverslips were incubated briefly with 50 ng/ml DAPI (Invitrogen), mounted with DABCO (Sigma), and sealed with nail polish.…”

Section: Microscopymentioning

confidence: 99%

“…However, although a general-purpose backup proteolytic system probably does not exist, presentation of some epitopes and peptide loading of some MHC-I alleles is not affected, or even enhanced, in the presence of proteasome inhibitors (reviewed in Ref. 4).…”

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confidence: 99%

Endoplasmic Reticulum Targeting Alters Regulation of Expression and Antigen Presentation of Proinsulin

Hsu

Janssen

Lawand

et al. 2014

The Journal of Immunology

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Peptide ligands presented by MHC class I (MHC-I) molecules are produced by degradation of cytosolic and nuclear, but also endoplasmic reticulum (ER)–resident, proteins by the proteasome. However, Ag processing of ER proteins remains little characterized. Studying processing and presentation of proinsulin, which plays a pivotal role in autoimmune diabetes, we found that targeting to the ER has profound effects not only on how proinsulin is degraded, but also on regulation of its cellular levels. While proteasome inhibition inhibited degradation and presentation of cytosolic proinsulin, as expected, it reduced the abundance of ER-targeted proinsulin. This targeting and protein modifications modifying protein half-life also had profound effects on MHC-I presentation and proteolytic processing of proinsulin. Thus, presentation of stable luminal forms was inefficient but enhanced by proteasome inhibition, whereas that of unstable luminal forms and of a cytosolic form were more efficient and compromised by proteasome inhibitors. Distinct stability of peptide MHC complexes produced from cytosolic and luminal proinsulin suggests that different proteolytic activities process the two Ag forms. Thus, both structural features and subcellular targeting of Ags can have strong effects on the processing pathways engaged by MHC-I–restricted Ags, and on the efficiency and regulation of their presentation.

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Post-proteasomal and proteasome-independent generation of MHC class I ligands

Cited by 66 publications

References 125 publications

The Effect of Proteasome Inhibition on the Generation of the Human Leukocyte Antigen (HLA) Peptidome

The Effect of Proteasome Inhibition on the Generation of the Human Leukocyte Antigen (HLA) Peptidome

The amino terminus extension in the long dipeptidyl peptidase 9 isoform contains a nuclear localization signal targeting the active peptidase to the nucleus

Endoplasmic Reticulum Targeting Alters Regulation of Expression and Antigen Presentation of Proinsulin

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