1199229_Liu,H_2022.pdf (3.26 MB)
Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86
journal contribution
posted on 2022-05-10, 00:00 authored by H Liu, KR Wilson, AM Firth, C Macri, P Schriek, AB Blum, J Villar, S Wormald, Mitch ShambrookMitch Shambrook, B Xu, HJ Lim, HEG McWilliam, Andrew HillAndrew Hill, LE Edgington-Mitchell, I Caminschi, MH Lahoud, E Segura, MJ Herold, JA Villadangos, JD MinternThe MARCH E3 ubiquitin (Ub) ligase MARCH1 regulates trafficking of major histocompatibility complex class II (MHC II) and CD86, molecules of critical importance to immunity. Here we show, using a genome-wide CRISPR knockout screen, that ubiquitin-like protein 3 (UBL3) is a necessary component of ubiquitination-mediated trafficking of these molecules in mice and in humans. Ubl3-deficient mice have elevated MHC II and CD86 expression on the surface of professional and atypical antigen presenting cells. UBL3 also regulates MHC II and CD86 in human dendritic cells (DCs) and macrophages. UBL3 impacts ubiquitination of MARCH1 substrates, a mechanism that requires UBL3 plasma membrane anchoring via prenylation. Loss of UBL3 alters adaptive immunity with impaired development of thymic regulatory T cells, loss of conventional type 1 DCs, increased number of trogocytic marginal zone B cells, and defective in vivo MHC II and MHC I antigen presentation. In summary, we identify UBL3 as a conserved, critical factor in MARCH1-mediated ubiquitination with important roles in immune responses.
Funding
We thank the Antibody Services Facility and Genomics Hub (Walter and Eliza Hall Institute) for the provision of reagents and expert assistance. We acknowledge the Melbourne Cytometry Platform from the Bio21 Institute node (University of Melbourne) for the provision of flow cytometry services. We acknowledge the Melbourne Mass Spectrometry and Proteomics Facility of the Bio21 Molecular Science and Biotechnology Institute at the University of Melbourne for the support of mass spectrometry analysis. We thank Satoshi Ishido (Hyogo College of Medicine, Nishinomiya, Japan) for providing the Marchf1-/- and Marchf8-/- mice. The generation of Ubl3-/- mice by CRISPR/Cas9 was performed by Andrew Kueh and Marco Herold (WEHI MAGEC laboratory). This work was supported by National Health and Medical Research Council, Australia grants and fellowships (1058193, 1154502, 1113293, and 1163090 [to J.A.V.], 1161101 and 1129672 [to J.D.M.], 2003192 [to H.E.G.McW], GNT1132604 [to A.F.H.], 1159658, 1186575, and 1156095 [to M.J.H.], and 1142358 [to M.H.L.]), Australian Research Council, Department of Education and Training grants or fellowships (110101383, 190102213, 170102471, 160103134 [to J.A.V.] and 190101242, 180100844, 160101373, and 180100521 [to J.D.M.], DE180100418 [to L.E.-M.]), the Leukemia and Lymphoma Society of America (LLS SCOR 7015-18 to M.J.H.), the Cancer Council of Victoria (1147328 and 2021 Grant In Aid to M.J.H.), and a Human Frontiers Science Program grant (0064/2011 [to J.A.V.]).
History
Publication Date
2022-12-01Journal
Nature CommunicationsVolume
13Issue
1Article Number
ARTN 1934Pagination
15p.Publisher
Springer NatureISSN
2041-1723Rights Statement
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.Publisher DOI
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Keywords
Science & TechnologyMultidisciplinary SciencesScience & Technology - Other TopicsMHC CLASS-IIMOUSE DENDRITIC CELLSPLASMA-MEMBRANEEXPRESSIONANTIGENSURFACEIDENTIFICATIONSELECTIONGENEMATURATIONAnimalsB7-2 AntigenDendritic CellsHistocompatibility Antigens Class IIMajor Histocompatibility ComplexMiceMice, Inbred C57BLUbiquitin-Protein LigasesUbiquitinationUbiquitinsImmunology