Post-Translational Peptide Splicing and T Cell Responses

Mishto, Michele; Liepe, Juliane

doi:10.1016/j.it.2017.07.011

Cited by 59 publications

(74 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We excluded trans-spliced peptides where the fragments stem from two different proteins for three reasons. First, all known spliced peptides are concatenated fragments from the same protein [15]. Second, the huge number of transspliced may lead to strongly increased false positive rates in subsequent bioinformatics analysis, and third, for trans-splicing to happen the two source proteins need to be present in the same proteasome at the same time, which is unlikely to happen on a large scale.…”

Section: Identification Of Possible Spliced-peptides Using Tagpepmentioning

confidence: 99%

Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome

Mylonas

Beer²,

Iseli

et al. 2018

Preprint

View full text Add to dashboard Cite

. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.Thecopyright holder for this preprint . http://dx.doi.org/10.1101/288209 doi: bioRxiv preprint first posted online Mar. 26, 2018; AbstractSpliced peptides are short protein fragments spliced together in the proteasome by peptide bond formation. True estimation of the contribution of proteasome-spliced peptides (PSPs) to the global Human Leukocyte Antigen (HLA) ligandome is critical. A recent study suggested that PSPs contribute up to 30% of the HLA ligandome. We performed a thorough reanalysis of the reported results using multiple computational tools and various validation steps and concluded that only a fraction of the proposed PSPs passes the quality filters. To better estimate the actual number of PSPs, we present an alternative workflow. We performed de-novo sequencing of the HLA-peptide spectra and discarded all de-novo sequences found in the UniProt database. We checked whether the remaining de-novo sequences could match spliced peptides from human proteins. The spliced sequences were appended to the UniProt fasta file, which was searched by two search tools at a FDR of 1%. We find that maximally 2-4% of the HLA ligandome could be explained as spliced protein fragments. The majority of these potential PSPs have good peptide-spectrum match properties and are predicted to bind the respective HLA molecules. However, it remains to be shown how many of these potential PSPs actually originate from proteasomal splicing events.

show abstract

Section: Identification Of Possible Spliced-peptides Using Tagpepmentioning

confidence: 99%

Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome

Mylonas

Beer²,

Iseli

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…We used 9- and 10-residue sliding windows to scan all protein sequences, since these are the optimum peptide lengths for binding to the HLA-A*02:01 groove (34). While spliced peptide epitopes (35) are not considered in the current study, this functionality can be added to our method at a later stage. Using NetMHCpan-4.0 (27), we identified all 439 9mer and 279 10mer epitopes that are predicted to yield positive (classified as both weak and strong) binders.…”

Section: Resultsmentioning

confidence: 99%

Structure-based modeling of SARS-CoV-2 peptide/HLA-A02 antigens

Nerli

Sgourakis

2020

Preprint

View full text Add to dashboard Cite

11As a first step toward the development of diagnostic and therapeutic tools to fight the Coronavirus 12 disease , it is important to characterize CD8+ T cell epitopes in the SARS-CoV-2 13 peptidome that can trigger adaptive immune responses. Here, we use RosettaMHC, a comparative 14 modeling approach which leverages existing high-resolution X-ray structures from peptide/MHC 15 complexes available in the Protein Data Bank, to derive physically realistic 3D models for high- 16affinity SARS-CoV-2 epitopes. We outline an application of our method to model 439 9mer and 17 279 10mer predicted epitopes displayed by the common allele HLA-A*02:01, and we make our 18 models publicly available through an online database (https://rosettamhc.chemistry.ucsc.edu). As 19 more detailed studies on antigen-specific T cell recognition become available, RosettaMHC 20 models of antigens from different strains and HLA alleles can be used as a basis to understand the 21 link between peptide/HLA complex structure and surface chemistry with immunogenicity, in the 22 context of SARS-CoV-2 infection. 24An ongoing pandemic caused by the novel SARS coronavirus (SARS-CoV-2) has become the 25 focus of extensive efforts to develop vaccines and antiviral therapies (1). Immune modulatory 26 interferons, which promote a widespread antiviral reaction in infected cells, and inhibition of pro-27 inflammatory cytokine function through anti-IL-6/IL-6R antibodies, have been proposed as 28 possible COVID-19 therapies (2, 3). However, stimulating a targeted T cell response against 29 specific viral antigens is hampered by a lack of detailed knowledge of the immunodominant 30 epitopes displayed by common Human Leukocyte Antigen (HLA) alleles across individuals 31 (public epitopes). The molecules of the class I major histocompatibility complex (MHC-I, or HLA 32 in humans) display on the cell surface a diverse pool of 8 to 15 amino acid peptides derived from 33 the endogenous processing of proteins expressed inside the cell (4). This MHC-I restriction of 34 peptide antigens provides jawed vertebrates with an essential mechanism for adaptive immunity: 35 surveillance of the displayed peptide/MHC-I (pMHC-I) molecules by CD8+ cytotoxic T-36 lymphocytes allows detection of aberrant protein expression patterns, which signify viral infection 37 and can trigger an adaptive immune response (5). A recent study has shown important changes in 38 T cell compartments during the acute phase of SARS-CoV-2 infection (6), suggesting that the 39 ability to quantify antigen-specific T cells would provide new avenues for understanding the 40 (which was not certified by peer review) : bioRxiv preprint 2 expansion and contraction of the TCR repertoire in different disease cohorts and clinical settings. 41Given the reduction in breadth and functionality of the naïve T cell repertoire during aging (7), 42 identifying a minimal set of viral antigens that can elicit a protective response will enable the 43 design of diagnostic tools to monitor critical gaps in the T cell repertoir...

show abstract

“…Reproduced with permission from ref. [ 5]. www.eji-journal.eu the gp100 209-217 epitope that is translocated into the endosomal pathway via an alternative route, the function of tapasin is not mandatory to efficiently present the gp100 209-217 epitope at the cell surface [54] (Fig.…”

Section: Discussionmentioning

confidence: 99%

ER‐aminopeptidase 1 determines the processing and presentation of an immunotherapy‐relevant melanoma epitope

et al. 2019

Self Cite

View full text Add to dashboard Cite

Dissecting the different steps of the processing and presentation of tumor-associated antigens is a key aspect of immunotherapies enabling to tackle the immune response evasion attempts of cancer cells. The immunodominant glycoprotein gp100 209-217 epitope, which is liberated from the melanoma differentiation antigen gp100 PMEL17 , is part of immunotherapy trials. By analyzing different human melanoma cell lines, we here demonstrate that a pool of N-terminal extended peptides sharing the common minimal epitope is generated by melanoma proteasome subtypes. In vitro and in cellulo experiments indicate that ER-resident aminopeptidase 1 (ERAP1)-but not ERAP2defines the processing of this peptide pool thereby modulating the T-cell recognition of melanoma cells. By combining the outcomes of our studies and others, we can sketch the Tumor immunology 271 complex processing and endogenous presentation pathway of the gp100 209-217 -containing epitope/peptides, which are produced by proteasomes and are translocated to the vesicular compartment through different pathways, where the precursor peptides that reach the endoplasmic reticulum are further processed by ERAP1. The latter step enhances the activation of epitope-specific T lymphocytes, which might be a target to improve the efficiency of anti-melanoma immunotherapy.Keywords: CD8 + T cells r proteasome r ER-aminopeptidase r melanoma r gp100Additional supporting information may be found online in the Supporting Information section at the end of the article.

show abstract

Post-Translational Peptide Splicing and T Cell Responses

Cited by 59 publications

References 86 publications

Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome

Estimating the Contribution of Proteasomal Spliced Peptides to the HLA-I Ligandome

Structure-based modeling of SARS-CoV-2 peptide/HLA-A02 antigens

ER‐aminopeptidase 1 determines the processing and presentation of an immunotherapy‐relevant melanoma epitope

Contact Info

Product

Resources

About