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A Systematic Interrogation of MHC Class I Antigen Presentation Identifies Constitutive and Compensatory Protein Degradation Pathways

Mamrosh, Jennifer L. and Li, Jing and Sherman, David J. and Moradian, Annie and Sweredoski, Michael J. and Verma, Rati and Johnston, James A. and Lipford, J. Russell and Deshaies, Raymond J. (2021) A Systematic Interrogation of MHC Class I Antigen Presentation Identifies Constitutive and Compensatory Protein Degradation Pathways. . (Unpublished) https://resolver.caltech.edu/CaltechAUTHORS:20211015-222209114

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Abstract

Protein degradation products are constitutively presented as peptide antigens by MHC Class I. While hypervariability of Class I genes is known to tremendously impact antigen presentation, whether differential function of protein degradation pathways (comprising >1000 genes) could alter antigen generation remains poorly understood apart from a few model substrates. In this study, we introduce normalization methods for quantitative antigen mass spectrometry and confirm that most Class I antigens are dependent on ubiquitination and proteasomal degradation. Remarkably, many antigens derived from mitochondrial inner membrane proteins are not. Additionally, we find that atypical antigens can arise from compensatory protein degradation pathways, such as an increase in mitochondrial and membrane protein antigen presentation upon proteasome inhibition. Notably, incomplete inhibition of protein degradation pathways may have clinical utility in cancer immunotherapy, as evidenced by appearance of novel antigens upon partial proteasome inhibition.


Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription
https://doi.org/10.1101/2021.10.07.463289DOIDiscussion Paper
ORCID:
AuthorORCID
Moradian, Annie0000-0002-0407-2031
Sweredoski, Michael J.0000-0003-0878-3831
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. JLM was previously supported by a Life Sciences Research Foundation postdoctoral fellowship funded by Astellas Pharma and is currently supported by Amgen’s Postdoctoral Fellows Program. At the outset of this work RJD was an Investigator of the Howard Hughes Medical Institute and was supported therefrom. We thank Karl Beutner for insightful discussions on MHC Class I and Chris Spahr for help with initial mass spectrometry experiments. We thank Brett Lomenick, Spiros Garbis, and Tsui-Fen Chou from Caltech’s Proteome Exploration Laboratory for running mass spectrometry experiments. The authors have declared no competing interest.
Funders:
Funding AgencyGrant Number
Life Sciences Research FoundationUNSPECIFIED
AmgenUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
DOI:10.1101/2021.10.07.463289
Record Number:CaltechAUTHORS:20211015-222209114
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20211015-222209114
Official Citation:A Systematic Interrogation of MHC Class I Antigen Presentation Identifies Constitutive and Compensatory Protein Degradation Pathways Jennifer L. Mamrosh, Jing Li, David J. Sherman, Annie Moradian, Michael J. Sweredoski, Rati Verma, James A. Johnston, J. Russell Lipford, Raymond J. Deshaies bioRxiv 2021.10.07.463289; doi: https://doi.org/10.1101/2021.10.07.463289
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:111486
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:19 Oct 2021 14:21
Last Modified:19 Oct 2021 14:21

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