A Major Role for TPPII in Trimming Proteasomal Degradation Products for MHC Class I Antigen Presentation

Reits, Eric; Neijssen, Joost; Herberts, Carla; Benckhuijsen, Willemien E.; Janssen, Lennert; Drijfhout, Jan W.; Neefjes, Jacques

doi:10.1016/s1074-7613(04)00074-3

Cited by 234 publications

(311 citation statements)

References 42 publications

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“…The K24 peptide, which was matched to two reported HLA class I epitopes, was found to have a correct C-terminus (Table 4). Three other peptides, K15, K20 and K26, matched to seven reported HLA class I epitopes would require generation of new C-termini (Table 4) potentially via the peptidase TPPII (Reits et al 2004). These results suggest that HSPA might chaperone peptides from the proteasome to TPPII, if necessary, and to the TAP complex which would then convey the peptides into the ER.…”

Section: Discussionmentioning

confidence: 99%

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Stocki

Morris

Preisinger

et al. 2010

Cell Stress and Chaperones

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Heat shock protein 70 (HSPA) is a molecular chaperone which has been suggested to shuttle human leukocyte antigen (HLA) epitope precursors from the proteasome to the transporter associated with antigen processing. Despite the reported observations that peptides chaperoned by HSPA are an effective source of antigens for cross-priming, little is known about the peptides involved in the process. In this study, we investigated the possible involvement of HSPA in HLA class I or class II antigen presentation and analysed the antigenic potential of the associated peptides. HSPA was purified from CCRF-CEM and K562 cell lines, and using mass spectrometry techniques, we identified 44 different peptides which were copurified with HSPA. The affinity of the identified peptides to two HSPA isoforms, HSPA1A and HSPA8, was confirmed using a peptide array. Four of the HSPAassociated peptides were matched with 13 previously reported HLA epitopes. Of these 13 peptides, nine were HLA class I and four were HLA class II epitopes. These results demonstrate the association of HSPA with HLA class I and class II epitopes, therefore providing further evidence for the involvement of HSPA in the antigen presentation process.

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Section: Discussionmentioning

confidence: 99%

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Stocki

Morris

Preisinger

et al. 2010

Cell Stress and Chaperones

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“…TPP II has been suggested to have the potential to operate in this capacity (26,30). However, there is currently no consensus on the precise role of TPP II in Ag processing since other reports support more of an accessory role for TPP II in the production of CTL epitopes (31,32). The second possible model is that the proteasome is an integral component in the presentation of epitopes such as NP [147][148][149][150][151][152][153][154][155] , even in the presence of proteasome inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that an AAF-cmk-sensitive proteolytic activity can contribute to the processing of NP 147-155 in normal cells and NP 147-155 and other epitopes in proteasome inhibitor adapted cells. TPP II is an obvious candidate for this processing activity given its role in compensating for chronic proteasome inhibition (25,26,29) and studies reporting a trimming (31,32) or proteasome-independent (30) processing role for this enzyme. However, AAF-cmk may affect other proteases and despite the potent inhibition of TPP II activity by AAF-cmk, epitope presentation was blocked by only ϳ10 -50% in adapted cells.…”

Section: Impact Of Aaf-cmk On Epitope Presentationmentioning

confidence: 99%

“…However, the capacity of cells with chronically impaired proteasomes to present specific peptides to CD8 T cells has not been completely addressed, and the contribution of up-regulated protease activities, including TPP II, to Ag processing under these conditions requires additional investigation. TPP II has been proposed to perform proteasome-independent processing (30) or proteasome-dependent trimming (31,32). Therefore, TPP II could account for the first steps in epitope generation under conditions of proteasome inhibition, or, alternatively, TPP II and/or additional proteases may trim proteasomal products to liberate precise epitopes and this activity may be more important when proteasome function is suboptimal.…”

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confidence: 99%

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Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Wherry

Golovina

Morrison

et al. 2006

The Journal of Immunology

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The proteasome is primarily responsible for the generation of MHC class I-restricted CTL epitopes. However, some epitopes, such as NP147–155 of the influenza nucleoprotein (NP), are presented efficiently in the presence of proteasome inhibitors. The pathways used to generate such apparently “proteasome-independent” epitopes remain poorly defined. We have examined the generation of NP147–155 and a second proteasome-dependent NP epitope, NP50–57, using cells adapted to growth in the presence of proteasome inhibitors and also through protease overexpression. We observed that: 1) Ag processing and presentation proceeds in proteasome-inhibitor adapted cells but may become more dependent, at least in part, on nonproteasomal protease(s), 2) tripeptidyl peptidase II does not substitute for the proteasome in the generation of NP147–155, 3) overexpression of leucine aminopeptidase, thymet oligopeptidase, puromycin-sensitive aminopeptidase, and bleomycin hydrolase, has little impact on the processing and presentation of NP50–57 or NP147–155, and 4) proteasome-inhibitor treatment altered the specificity of substrate cleavage by the proteasome using cell-free digests favoring NP147–155 epitope preservation. Based on these results, we propose a central role for the proteasome in epitope generation even in the presence of proteasome inhibitors, although such inhibitors will likely alter cleavage patterns and may increase the dependence of the processing pathway on postproteasomal enzymes.

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“…6B). Considering that TPPII is known both to act as an enzyme trimming epitope precursors (30) and to generate some epitopes (reviewed in Ref. 5), we tested butabindide, a more specific TPPII inhibitor.…”

Section: Possible Role Of Alternative Pathways In Presentation Of Pi mentioning

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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A Major Role for TPPII in Trimming Proteasomal Degradation Products for MHC Class I Antigen Presentation

Cited by 234 publications

References 42 publications

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Identification of potential HLA class I and class II epitope precursors associated with heat shock protein 70 (HSPA)

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

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

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