Ubiquitin-like protein 3 (UBL3) is required for MARCH ubiquitination of major histocompatibility complex class II and CD86

Haiyin Liu, Kayla R. Wilson, Ashley M. Firth, Christophe Macri, Patrick Schriek, Annabelle B. Blum, Javiera Villar, Samuel Wormald, Mitch Shambrook, Bangyan Xu, Hui Jing Lim, Hamish E. G. McWilliam, Andrew F. Hill, Laura E. Edgington-Mitchell, Irina Caminschi, Mireille H. Lahoud, Elodie Segura, Marco J. Herold, Jose A. Villadangos () and Justine D. Mintern ()
Additional contact information
Haiyin Liu: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Kayla R. Wilson: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Ashley M. Firth: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Christophe Macri: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Patrick Schriek: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Annabelle B. Blum: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Javiera Villar: PSL Research University, INSERM, U932
Samuel Wormald: The Walter and Eliza Hall Institute of Medical Research
Mitch Shambrook: La Trobe University
Bangyan Xu: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Hui Jing Lim: The University of Melbourne
Hamish E. G. McWilliam: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Andrew F. Hill: La Trobe University
Laura E. Edgington-Mitchell: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Irina Caminschi: Monash University
Mireille H. Lahoud: Monash University
Elodie Segura: PSL Research University, INSERM, U932
Marco J. Herold: The Walter and Eliza Hall Institute of Medical Research
Jose A. Villadangos: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute
Justine D. Mintern: The University of Melbourne, Bio21 Molecular Science and Biotechnology Institute

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract The 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.

Date: 2022
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DOI: 10.1038/s41467-022-29524-w

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