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...
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| Format: | Article |
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Frontiers Media S.A.
2018-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01920/full |
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| author | Sarah C. Moser Jane S. A. Voerman Dennis L. Buckley Georg E. Winter Christopher Schliehe |
| author_facet | Sarah C. Moser Jane S. A. Voerman Dennis L. Buckley Georg E. Winter Christopher Schliehe |
| author_sort | Sarah C. Moser |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T04:36:55Z |
| format | Article |
| id | doaj.art-ac817bc80a274899b68b42ffba9b002a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T04:36:55Z |
| publishDate | 2018-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ac817bc80a274899b68b42ffba9b002a2022-12-21T17:59:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-01-01810.3389/fimmu.2017.01920303933Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I MoleculesSarah C. Moser0Jane S. A. Voerman1Dennis L. Buckley2Georg E. Winter3Christopher Schliehe4Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsDepartment of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsDepartment for Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United StatesCeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, AustriaDepartment of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, NetherlandsBifunctional 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.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01920/fullMHC class Iantigen presentationbifunctional degradersPROTACsprotein degradationDRiPs |
| spellingShingle | Sarah C. Moser Jane S. A. Voerman Dennis L. Buckley Georg E. Winter Christopher Schliehe Acute Pharmacologic Degradation of a Stable Antigen Enhances Its Direct Presentation on MHC Class I Molecules Frontiers in Immunology MHC class I antigen presentation bifunctional degraders PROTACs protein degradation DRiPs |
| 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 | MHC class I antigen presentation bifunctional degraders PROTACs protein degradation DRiPs |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01920/full |
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