Cargando…

Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules

Bifunctional degraders, also referred to as proteolysis-targeting chimeras (PROTACs), are a recently developed class of small molecules. They were designed to specifically target endogenous proteins for ubiquitin/proteasome-dependent degradation and to thereby interfere with pathological mechanisms...

Descripción completa

Detalles Bibliográficos
Autores principales: Moser, Sarah C., Voerman, Jane S. A., Buckley, Dennis L., Winter, Georg E., Schliehe, Christopher
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766668/
https://www.ncbi.nlm.nih.gov/pubmed/29358938
http://dx.doi.org/10.3389/fimmu.2017.01920
_version_ 1783292402761465856
author Moser, Sarah C.
Voerman, Jane S. A.
Buckley, Dennis L.
Winter, Georg E.
Schliehe, Christopher
author_facet Moser, Sarah C.
Voerman, Jane S. A.
Buckley, Dennis L.
Winter, Georg E.
Schliehe, Christopher
author_sort Moser, Sarah C.
collection PubMed
description Bifunctional degraders, also referred to as proteolysis-targeting chimeras (PROTACs), are a recently developed class of small molecules. They were designed to specifically target endogenous proteins for ubiquitin/proteasome-dependent degradation and to thereby interfere with pathological mechanisms of diseases, including cancer. In this study, we hypothesized that this process of acute pharmacologic protein degradation might increase the direct MHC class I presentation of degraded targets. By studying this question, we contribute to an ongoing discussion about the origin of peptides feeding the MHC class I presentation pathway. Two scenarios have been postulated: peptides can either be derived from homeostatic turnover of mature proteins and/or from short-lived defective ribosomal products (DRiPs), but currently, it is still unclear to what ratio and efficiency both pathways contribute to the overall MHC class I presentation. We therefore generated the intrinsically stable model antigen GFP-S8L-F12 that was susceptible to acute pharmacologic degradation via the previously described degradation tag (dTAG) system. Using different murine cell lines, we show here that the bifunctional molecule dTAG-7 induced rapid proteasome-dependent degradation of GFP-S8L-F12 and simultaneously increased its direct presentation on MHC class I molecules. Using the same model in a doxycycline-inducible setting, we could further show that stable, mature antigen was the major source of peptides presented, thereby excluding a dominant role of DRiPs in our system. This study is, to our knowledge, the first to investigate targeted pharmacologic protein degradation in the context of antigen presentation and our data point toward future applications by strategically combining therapies using bifunctional degraders with their stimulating effect on direct MHC class I presentation.
format Online
Article
Text
id pubmed-5766668
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-57666682018-01-22 Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules Moser, Sarah C. Voerman, Jane S. A. Buckley, Dennis L. Winter, Georg E. Schliehe, Christopher Front Immunol Immunology Bifunctional degraders, also referred to as proteolysis-targeting chimeras (PROTACs), are a recently developed class of small molecules. They were designed to specifically target endogenous proteins for ubiquitin/proteasome-dependent degradation and to thereby interfere with pathological mechanisms of diseases, including cancer. In this study, we hypothesized that this process of acute pharmacologic protein degradation might increase the direct MHC class I presentation of degraded targets. By studying this question, we contribute to an ongoing discussion about the origin of peptides feeding the MHC class I presentation pathway. Two scenarios have been postulated: peptides can either be derived from homeostatic turnover of mature proteins and/or from short-lived defective ribosomal products (DRiPs), but currently, it is still unclear to what ratio and efficiency both pathways contribute to the overall MHC class I presentation. We therefore generated the intrinsically stable model antigen GFP-S8L-F12 that was susceptible to acute pharmacologic degradation via the previously described degradation tag (dTAG) system. Using different murine cell lines, we show here that the bifunctional molecule dTAG-7 induced rapid proteasome-dependent degradation of GFP-S8L-F12 and simultaneously increased its direct presentation on MHC class I molecules. Using the same model in a doxycycline-inducible setting, we could further show that stable, mature antigen was the major source of peptides presented, thereby excluding a dominant role of DRiPs in our system. This study is, to our knowledge, the first to investigate targeted pharmacologic protein degradation in the context of antigen presentation and our data point toward future applications by strategically combining therapies using bifunctional degraders with their stimulating effect on direct MHC class I presentation. Frontiers Media S.A. 2018-01-08 /pmc/articles/PMC5766668/ /pubmed/29358938 http://dx.doi.org/10.3389/fimmu.2017.01920 Text en Copyright © 2018 Moser, Voerman, Buckley, Winter and Schliehe. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Moser, Sarah C.
Voerman, Jane S. A.
Buckley, Dennis L.
Winter, Georg E.
Schliehe, Christopher
Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules
title Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules
title_full Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules
title_fullStr Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules
title_full_unstemmed Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules
title_short Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules
title_sort acute pharmacologic degradation of a stable antigen enhances its direct presentation on mhc class i molecules
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5766668/
https://www.ncbi.nlm.nih.gov/pubmed/29358938
http://dx.doi.org/10.3389/fimmu.2017.01920
work_keys_str_mv AT mosersarahc acutepharmacologicdegradationofastableantigenenhancesitsdirectpresentationonmhcclassimolecules
AT voermanjanesa acutepharmacologicdegradationofastableantigenenhancesitsdirectpresentationonmhcclassimolecules
AT buckleydennisl acutepharmacologicdegradationofastableantigenenhancesitsdirectpresentationonmhcclassimolecules
AT wintergeorge acutepharmacologicdegradationofastableantigenenhancesitsdirectpresentationonmhcclassimolecules
AT schliehechristopher acutepharmacologicdegradationofastableantigenenhancesitsdirectpresentationonmhcclassimolecules