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PreprintCited by 2Ubiquitin and proteasome pathwaysImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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Major histocompatibility class II in murine antigen presenting cells is modified with a branched K63 and K11-linked ubiquitin chain

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Liu, Haiyin, Francis, Lauren, Dagley, Laura F., Cobbold, Simon A., Webb, Andrew I., Komander, David, Villadangos, Jose A, Mintern, Justine D.·2025·Scientific Reports
DOI 10.21203/rs.3.rs-6763007/v1

Preprint — published as 10.1038/s41598-025-25817-4 · Paper page

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Abstract

Major histocompatibility class II (MHC II) is critical for adaptive immunity. MHC II intracellular trafficking and degradation is regulated by ubiquitination, with poly-ubiquitination (Ub) of MHC II directing it away from the plasma membrane. The MHC II poly-Ub chain that dictates the fate and function of ubiquitinated MHC II has not been characterized. Here, we describe the poly-Ub chain associated with MHC II in primary conventional dendritic cells (cDCs) and B cells. Analysis was conducted for endogenous H2-A and H2-E molecules immunoprecipitated from primary cells. We show that the ubiquitination of both I-A and I-E expressed by cDCs and B cells is dependent on the E3 Ub ligase MARCH1. Comprehensive Ub chain analysis reveals the MARCH1-dependent poly-Ub chain that is associated with MHC II is composed of a branched chain with K11 and K63 Ub chain linkages. This is the first description of the Ub chain architecture associated with MARCH1-mediated ubiquitination of MHC II in primary antigen presenting cells.

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Metadata

Authors
Liu, H., Francis, L., Dagley, L. F., Cobbold, S. A., Webb, A. I., Komander, D., Villadangos, J. A., & Mintern, J. D.
Affiliations
  • The University of Melbourne (AU)
  • The University of Melbourne
Corresponding author
Mintern, Justine D.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2025-07-09
Volume
15
Issue
1
Pages
41884-41884
ISSN
2045-2322 (ISSN-L)
DOI
10.21203/rs.3.rs-6763007/v1
OpenAlex
W4416666706
Cited by
2
References
1
Citations by year
2026: 2
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by-nc-nd)
Funders
  • Human Frontier Science Program
  • Medical Research Council
  • Australian Research Council
  • National Health and Medical Research Council (1058193, 1154502, 1016629)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
MHC class II, ubiquitination, polyubiquitin chains, K63-linked ubiquitin, branched ubiquitin chains, MARCH1, E3 ubiquitin ligase, antigen-presenting cells, myeloid dendritic cells, B cells, I-A, I-E, adaptive immunity
MeSH terms
Animals, Antigen-Presenting Cells, Histocompatibility Antigens Class II, B-Lymphocytes, Dendritic Cells, Mice, Inbred C57BL, Ubiquitin, Ubiquitin-Protein Ligases, Mice, Ubiquitination

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